{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:44:45Z","timestamp":1787964285017,"version":"build-2784847793"},"reference-count":139,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related mortality worldwide despite substantial therapeutic improvements over the past two decades. Advances in the understanding of colorectal tumor biology and oncogenic signaling have enabled the development of biomarker-guided therapies targeting alterations in EGFR, BRAFV600E, KRAS mutations and HER2 amplifications, improving outcomes in selected patient populations. Nevertheless, the emergence of both intrinsic and acquired resistance mechanisms continues to limit the durability of these responses. Resistance to targeted therapies in mCRC arises through multiple, often convergent mechanisms, including activation of compensatory signaling pathways, pre-existing genomic heterogeneity, and therapy-driven clonal selection. The integration of molecular profiling into clinical decision-making is essential to guide treatment selection and optimize therapeutic sequencing, ultimately enabling progress in precision oncology. Advances in genomic technologies, particularly circulating tumor DNA (ctDNA) analysis, have allowed longitudinal monitoring of tumor evolution, providing important insights into the mechanisms underlying resistance to targeted therapies. The aim of this review is to summarize the genomic landscape of mCRC and discuss current targeted therapeutic strategies in molecularly defined subgroups, with a particular focus on the mechanisms driving primary and acquired resistance.<\/jats:p>","DOI":"10.3390\/genes17040460","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T10:30:23Z","timestamp":1776249023000},"page":"460","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genomic Landscape, Targeted Therapies, and Mechanisms of Resistance in Molecularly Selected Metastatic Colorectal Cancer Patients"],"prefix":"10.3390","volume":"17","author":[{"given":"Patricia","family":"Garcia Pastor","sequence":"first","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Saoudi Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9240-4907","authenticated-orcid":false,"given":"Francesc","family":"Salva","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8137-5415","authenticated-orcid":false,"given":"Javier","family":"Ros","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3500-9641","authenticated-orcid":false,"given":"Iosune","family":"Baraibar","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1935-0951","authenticated-orcid":false,"given":"Marta","family":"Rodr\u00edguez Castells","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Salva de Torres","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariadna","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5976-3312","authenticated-orcid":false,"given":"Adriana","family":"Alcaraz","sequence":"additional","affiliation":[{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5023-3521","authenticated-orcid":false,"given":"Caterina","family":"Vaghi","sequence":"additional","affiliation":[{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"},{"name":"Department of Hematology, Oncology, and Molecular Medicine, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Piazza Ospedale Maggiore, 3, 20162 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-8139","authenticated-orcid":false,"given":"Josep","family":"Tabernero","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Elez","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Vall d\u2019Hebron University Hospital, 08035 Barcelona, Spain"},{"name":"Colorectal Cancer Group, Digestive Tumors Group, Vall d\u2019Hebron Institute of Oncology, VHIO, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer Statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","first-page":"229","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S0140-6736(24)00360-X","article-title":"Colorectal Cancer","volume":"404","author":"Eng","year":"2024","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1001\/jama.2021.0106","article-title":"Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review","volume":"325","author":"Biller","year":"2021","journal-title":"JAMA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"101737","DOI":"10.1016\/j.xcrm.2024.101737","article-title":"Early-Onset Cancers: Biological Bases and Clinical Implications","volume":"5","author":"Mauri","year":"2024","journal-title":"Cell Rep. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1038\/s41568-025-00872-1","article-title":"The Immune Microenvironment of Colorectal Cancer","volume":"25","author":"Kennel","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hanahan, D. (2026). Hallmarks of Cancer\u2014Then and Now, and Beyond. Cell.","DOI":"10.1016\/j.cell.2025.12.049"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41392-024-01953-7","article-title":"Signaling Pathways Involved in Colorectal Cancer: Pathogenesis and Targeted Therapy","volume":"9","author":"Li","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/nm.3967","article-title":"The Consensus Molecular Subtypes of Colorectal Cancer","volume":"21","author":"Guinney","year":"2015","journal-title":"Nat. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3552","DOI":"10.1200\/JCO.2024.42.16_suppl.3552","article-title":"Real-World Use of Anti-EGFR Therapy in Metastatic Colorectal Cancer","volume":"42","author":"Robinson","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Manzi, J., Hoff, C.O., Ferreira, R., Pimentel, A., Datta, J., Livingstone, A.S., Vianna, R., and Abreu, P. (2023). Targeted Therapies in Colorectal Cancer: Recent Advances in Biomarkers, Landmark Trials, and Future Perspectives. Cancers, 15.","DOI":"10.3390\/cancers15113023"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"El Hage, M., Su, Z., and Linnebacher, M. (2025). Addressing Challenges in Targeted Therapy for Metastatic Colorectal Cancer. Cancers, 17.","DOI":"10.3390\/cancers17071098"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41392-020-0116-z","article-title":"Comprehensive Review of Targeted Therapy for Colorectal Cancer","volume":"5","author":"Xie","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/S2468-1253(23)00479-X","article-title":"Targeting the EGFR Signalling Pathway in Metastatic Colorectal Cancer","volume":"9","author":"Napolitano","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Salva de Torres, C., Baraibar, I., Saoudi Gonz\u00e1lez, N., Ros, J., Salva, F., Rodr\u00edguez-Castells, M., Alcaraz, A., Garc\u00eda, A., Tabernero, J., and \u00c9lez, E. (2024). Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25136967"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1186\/s13046-021-02130-2","article-title":"Resistance to Anti-EGFR Therapies in Metastatic Colorectal Cancer: Underlying Mechanisms and Reversal Strategies","volume":"40","author":"Zhou","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Foncillas, J., Sunakawa, Y., Aderka, D., Wainberg, Z., Ronga, P., Witzler, P., and Stintzing, S. (2019). Distinguishing Features of Cetuximab and Panitumumab in Colorectal Cancer and Other Solid Tumors. Front. Oncol., 9.","DOI":"10.3389\/fonc.2019.00849"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1001\/jama.2023.4428","article-title":"Panitumumab vs Bevacizumab Added to Standard First-Line Chemotherapy and Overall Survival Among Patients with RAS Wild-Type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial","volume":"329","author":"Watanabe","year":"2023","journal-title":"JAMA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1093\/annonc\/mdy140","article-title":"Primary Tumor Sidedness and Benefit from FOLFOXIRI plus Bevacizumab as Initial Therapy for Metastatic Colorectal Cancer. Retrospective Analysis of the TRIBE Trial by GONO","volume":"29","author":"Cremolini","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2200037","DOI":"10.1200\/PO.22.00037","article-title":"Negative Ultraselection of Patients with RAS\/BRAF Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer Receiving Anti\u2013EGFR-Based Therapy","volume":"6","author":"Randon","year":"2022","journal-title":"JCO Precis. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ccell.2019.05.013","article-title":"Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer","volume":"36","author":"Woolston","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1158\/2159-8290.CD-11-0109","article-title":"A Molecularly Annotated Platform of Patient-Derived Xenografts (\u201cxenopatients\u201d) Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer","volume":"1","author":"Bertotti","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5263","DOI":"10.1200\/JCO.23.00506","article-title":"Initial Panitumumab plus Fluorouracil, Leucovorin, and Oxaliplatin or plus Fluorouracil and Leucovorin in Elderly Patients with RAS and BRAF Wild-Type Metastatic Colorectal Cancer: The PANDA Trial by the GONO Foundation","volume":"41","author":"Lonardi","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1158\/1078-0432.CCR-23-3023","article-title":"Negative Hyperselection of Resistance Mutations for Panitumumab Maintenance in RAS Wild-Type Metastatic Colorectal Cancer (PanaMa Phase II Trial, AIO KRK 0212)","volume":"30","author":"Stahler","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"115399","DOI":"10.1016\/j.ejca.2025.115399","article-title":"Molecular Hyperselection for Optimal Choice of First-Line Targeted Therapy Independent of Primary Tumor Sidedness: An Exploratory Analysis of the Randomized FIRE-3 Study Performed in RAS Wild-Type Metastatic Colorectal Cancer","volume":"221","author":"Weiss","year":"2025","journal-title":"Eur. J. Cancer"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1038\/s41591-023-02791-w","article-title":"Baseline CtDNA Gene Alterations as a Biomarker of Survival after Panitumumab and Chemotherapy in Metastatic Colorectal Cancer","volume":"30","author":"Shitara","year":"2024","journal-title":"Nat. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Oh, J.M., Kim, S., Tsung, C., Kent, E., Jain, A., Ruff, S.M., and Zhang, H. (2025). Comprehensive Review of the Resistance Mechanisms of Colorectal Cancer Classified by Therapy Type. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1571731"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"TPS3633","DOI":"10.1200\/JCO.2022.40.16_suppl.TPS3633","article-title":"A Biomarker Enrichment Trial of Anti-EGFR Agents in Right Primary Tumor Location (RPTL), RAS Wild-Type (RAS-Wt) Advanced Colorectal Cancer (ACRC): ARIEL (ISRCTN11061442)","volume":"40","author":"Williams","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.3390\/onco4040019","article-title":"Exploring the Potential of Epiregulin and Amphiregulin as Prognostic, Predictive, and Therapeutic Targets in Colorectal Cancer","volume":"4","author":"High","year":"2024","journal-title":"Onco"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nm.2609","article-title":"Identification of a Mutation in the Extracellular Domain of the Epidermal Growth Factor Receptor Conferring Cetuximab Resistance in Colorectal Cancer","volume":"18","author":"Montagut","year":"2012","journal-title":"Nat. Med."},{"key":"ref_31","first-page":"29","article-title":"MM-151 Overcomes Acquired Resistance to Cetuximab and Panitumumab in Colorectal Cancers Harboring EGFR Extracellular Domain Mutations","volume":"1","author":"Ma","year":"2023","journal-title":"Nov. Sensitizing Agents Ther. Anti-EGFR Antibodies Break. Toler. Antib.-Mediat. Immunother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"926","DOI":"10.3748\/wjg.v29.i6.926","article-title":"Resistance to Targeted Therapy in Metastatic Colorectal Cancer: Current Status and New Developments","volume":"29","author":"Tang","year":"2023","journal-title":"World J. Gastroenterol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/bjc.2015.480","article-title":"Phase II Study of Necitumumab plus Modified FOLFOX6 as First-Line Treatment in Patients with Locally Advanced or Metastatic Colorectal Cancer","volume":"114","author":"Elez","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, Q., Shen, X., Chen, G., and Du, J. (2022). Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers, 14.","DOI":"10.3390\/cancers14122928"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1158\/2159-8290.CD-12-0558","article-title":"Amplification of the MET Receptor Drives Resistance to Anti-EGFR Therapies in Colorectal Cancer","volume":"3","author":"Bardelli","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"TPS3636","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS3636","article-title":"OrigAMI-2: A Randomized, Phase 3 Study of Amivantamab vs Cetuximab, Both in Combination with FOLFOX or FOLFIRI, as First-Line Treatment in Left-Sided RAS\/BRAF Wild-Type Metastatic Colorectal Cancer","volume":"43","author":"Arnold","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1158\/2159-8290.CD-25-0679","article-title":"A Plastic EMP1+ to LGR5+ Cell State Conversion as a Bypass to KRASG12D Pharmacologic Inhibition in Metastatic Colorectal Cancer","volume":"16","author":"Centonze","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Lundberg, A.S., Geuijen, C.A.W., Hill, S., Lammerts van Bueren, J.J., Fumagalli, A., de Kruif, J., Silverman, P.B., and Tabernero, J. (2025). Petosemtamab, a Bispecific Antibody Targeting Epidermal Growth Factor Receptor (EGFR) and Leucine-Rich G Repeat-Containing Protein-Coupled Receptor (LGR5) Designed for Broad Clinical Applications. Cancers, 17.","DOI":"10.3390\/cancers17101665"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Parseghian, C., Eluri, M., Kopetz, S., and Raghav, K. (2023). Mechanisms of Resistance to EGFR-Targeted Therapies in Colorectal Cancer: More than Just Genetics. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1176657"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"S27","DOI":"10.1016\/j.annonc.2025.05.056","article-title":"44P Rechallenge with Anti-HER2 Regimens in Metastatic Colorectal Cancer: The Retrospective RHEA Study","volume":"36","author":"Bianchi","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Leite, L.F., Noronha, M.M., de Menezes, J.S.A., da Concei\u00e7\u00e3o, L.D., Almeida, L.F.C., Cappellaro, A.P., Belotto, M., Biachi de Castria, T., Peixoto, R.D., and Megid, T.B.C. (2025). Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance. Cancers, 17.","DOI":"10.3390\/cancers17172804"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/nm.3870","article-title":"Clonal Evolution and Resistance to EGFR Blockade in the Blood of Colorectal Cancer Patients","volume":"21","author":"Siravegna","year":"2015","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ctrv.2018.12.006","article-title":"Retreatment with Anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer: Systematic Review of Different Strategies","volume":"73","author":"Mauri","year":"2019","journal-title":"Cancer Treat. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100120","DOI":"10.1016\/j.esmogo.2024.100120","article-title":"Anti-EGFR Re-Challenge with Chemotherapy in RAS Wild-Type Advanced Colorectal Cancer (A-REPEAT Study): Efficacy and Correlations with Tissue and Plasma Genotyping","volume":"7","author":"Sgouros","year":"2025","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"102023","DOI":"10.1016\/j.ctrv.2020.102023","article-title":"Resistance to Anti-Epidermal Growth Factor Receptor in Metastatic Colorectal Cancer: What Does Still Need to Be Addressed?","volume":"86","author":"Martini","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1001\/jamaoncol.2018.5080","article-title":"Rechallenge for Patients with RAS and BRAF Wild-Type Metastatic Colorectal Cancer with Acquired Resistance to First-Line Cetuximab and Irinotecan: A Phase 2 Single-Arm Clinical Trial","volume":"5","author":"Cremolini","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3506","DOI":"10.1200\/JCO.2021.39.15_suppl.3506","article-title":"Phase II Study of Anti-EGFR Rechallenge Therapy with Panitumumab Driven by Circulating Tumor DNA Molecular Selection in Metastatic Colorectal Cancer: The CHRONOS Trial","volume":"39","author":"Pietrantonio","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"S477","DOI":"10.1016\/j.annonc.2025.08.1303","article-title":"728MO Predictive Value of Low-Frequency Resistance Mutations and Relative Mutant Allele Frequencies (RMAFs) in Anti-EGFR Rechallenge for RAS\/BRAF Wild-Type (Wt) Metastatic Colorectal Cancer (MCRC)","volume":"36","author":"Comas","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"S26","DOI":"10.1016\/j.annonc.2025.05.054","article-title":"42P Real-World Outcomes of Anti-EGFR Rechallenge in RAS\/BRAF Wild-Type (Wt) Metastatic Colorectal Cancer (MCRC)","volume":"36","author":"Comas","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e245635","DOI":"10.1001\/jamanetworkopen.2024.5635","article-title":"Anti-EGFR Rechallenge in Patients with Refractory CtDNA RAS\/BRAF Wt Metastatic Colorectal Cancer: A Nonrandomized Controlled Trial","volume":"7","author":"Ciardiello","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"4530","DOI":"10.1158\/1078-0432.CCR-23-0079","article-title":"Circulating Tumor DNA to Drive Treatment in Metastatic Colorectal Cancer","volume":"29","author":"Patelli","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1200\/EDBK_349561","article-title":"The Evolving Treatment Landscape in BRAF-V600E\u2013Mutated Metastatic Colorectal Cancer","volume":"42","author":"Tabernero","year":"2022","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1200\/JCO.2016.71.4394","article-title":"Non-V600 BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer","volume":"35","author":"Jones","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","article-title":"Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation","volume":"364","author":"Chapman","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1056\/NEJMoa1502309","article-title":"Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations","volume":"373","author":"Hyman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3534","DOI":"10.1200\/jco.2010.28.15_suppl.3534","article-title":"PLX4032 in Metastatic Colorectal Cancer Patients with Mutant BRAF Tumors","volume":"28","author":"Kopetz","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nature10868","article-title":"Unresponsiveness of Colon Cancer to BRAF(V600E) Inhibition Through Feedback Activation of EGFR","volume":"483","author":"Prahallad","year":"2012","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1158\/2159-8290.CD-11-0341","article-title":"EGFR-Mediated Re-Activation of MAPK Signaling Contributes to Insensitivity of BRAF Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib","volume":"2","author":"Corcoran","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1056\/NEJMoa1908075","article-title":"Encorafenib, Binimetinib, and Cetuximab in BRAF V600E\u2013Mutated Colorectal Cancer","volume":"381","author":"Kopetz","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1038\/s41591-024-03235-9","article-title":"Molecular Profiling of BRAF-V600E-Mutant Metastatic Colorectal Cancer in the Phase\u20093 BEACON CRC Trial","volume":"30","author":"Kopetz","year":"2024","journal-title":"Nat. Med."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1056\/NEJMoa2501912","article-title":"Encorafenib, Cetuximab, and MFOLFOX6 in BRAF -Mutated Colorectal Cancer","volume":"392","author":"Elez","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1038\/s41591-022-01976-z","article-title":"RNF43 Mutations Predict Response to Anti-BRAF\/EGFR Combinatory Therapies in BRAFV600E Metastatic Colorectal Cancer","volume":"28","author":"Elez","year":"2022","journal-title":"Nat. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.annonc.2023.02.016","article-title":"Plasmatic BRAF-V600E Allele Fraction as a Prognostic Factor in Metastatic Colorectal Cancer Treated with BRAF Combinatorial Treatments","volume":"34","author":"Ros","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_64","unstructured":"(2026, February 28). Study Details. NCT07178717. A Study to Characterize Encorafenib plus Cetuximab as Rechallenge Treatment for BRAF V600E-Mutant Metastatic Colorectal Cancer Patients After Previous Therapy with BRAF Inhibitors-Based Combinations. ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT07178717."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.annonc.2023.10.120","article-title":"Circulating Tumor DNA, and Clinical Features to Guide Rechallenge with BRAF Inhibitors in BRAF-V600E Mutated Metastatic Colorectal Cancer","volume":"35","author":"Ros","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_66","first-page":"267","article-title":"Rechallenge with BRAF and Anti-EGFR Inhibitors in Patients with Metastatic Colorectal Cancer Harboring BRAFV600E Mutation Who Progressed on Cetuximab and Encorafenib with or Without Binimetinib: A Case Series","volume":"21","author":"Ji","year":"2022","journal-title":"Clin. Color. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1016\/j.ccell.2025.08.002","article-title":"Phase 1\/2 Trial of Encorafenib, Cetuximab, and Nivolumab in Microsatellite Stable BRAFV600E Metastatic Colorectal Cancer","volume":"43","author":"Morris","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/s41591-022-02181-8","article-title":"Combined PD-1, BRAF and MEK Inhibition in BRAFV600E Colorectal Cancer: A Phase 2 Trial","volume":"29","author":"Tian","year":"2023","journal-title":"Nat. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"653","DOI":"10.2217\/fon-2022-1249","article-title":"SEAMARK: Phase II Study of First-Line Encorafenib and Cetuximab plus Pembrolizumab for MSI-H\/DMMR BRAF V600E-Mutant MCRC","volume":"20","author":"Elez","year":"2024","journal-title":"Future Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1007\/s00262-025-04005-3","article-title":"Antitumor Effects of Immunotherapy Combined with BRAF and MEK Inhibitors in BRAF V600E Metastatic Colorectal Cancer","volume":"74","author":"Tak","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Guerrero, P., Albarr\u00e1n, V., San Rom\u00e1n, M., Gonz\u00e1lez-Merino, C., Garc\u00eda de Quevedo, C., Moreno, J., Calvo, J.C., Gonz\u00e1lez, G., Orejana, I., and Chamorro, J. (2023). BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature. Cancers, 15.","DOI":"10.3390\/cancers15215243"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1158\/2159-8290.CD-16-0297","article-title":"MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer","volume":"6","author":"Pietrantonio","year":"2016","journal-title":"Cancer Discov."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S478","DOI":"10.1016\/j.annonc.2025.08.1304","article-title":"729MO Circulating Tumour (Ct) DNA Analysis of BRAF V600E Dynamics and Changes in Genomic Landscape in Patients (Pts) with First-Line (1L) BRAF V600E-Mutant Metastatic Colorectal Cancer (MCRC) Treated in BREAKWATER","volume":"36","author":"Kopetz","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_74","unstructured":"(2026, February 28). Study Details. NCT05743036. ZN-C3 in Adult Participants with Metastatic Colorectal Cancer. ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05743036."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1158\/2159-8290.CD-24-0024","article-title":"A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation","volume":"14","author":"Yaeger","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1038\/s41467-026-69216-3","article-title":"Pan-RAF Inhibitor Exarafenib Targets BRAF Class II\/III NSCLC and Reveals ARAF-KSR1 Resistance and Combination Strategies","volume":"17","author":"Manabe","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2700","DOI":"10.1158\/1535-7163.MCT-15-0136-T","article-title":"Combined Pan-RAF and MEK Inhibition Overcomes Multiple Resistance Mechanisms to Selective RAF Inhibitors","volume":"14","author":"Whittaker","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_78","unstructured":"(2026, February 28). Study Details. NCT05355701. A Study to Learn About the Study Medicine Called PF-07799933 in People with Advanced Solid Tumors with BRAF Alterations. ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05355701."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Chapdelaine, A.G., Ku, G.C., Sun, G., and Ayrapetov, M.K. (2023). The Targeted Degradation of BRAF V600E Reveals the Mechanisms of Resistance to BRAF-Targeted Treatments in Colorectal Cancer Cells. Cancers, 15.","DOI":"10.3390\/cancers15245805"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1158\/0008-5472.CAN-25-4381","article-title":"Overcoming the Limits of Inhibition: Mutant-Selective BRAF Degraders","volume":"86","author":"Chen","year":"2026","journal-title":"Cancer Res."},{"key":"ref_81","unstructured":"(2026, February 28). Study Details. NCT05668585. A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 as Monotherapy and Combination Therapy in Subjects with BRAF V600 Mutant Solid Tumors. ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05668585."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"166061","DOI":"10.1016\/j.bbadis.2020.166061","article-title":"BRAF Paradox Breakers PLX8394, PLX7904 Are More Effective against BRAFV600\u0395 CRC Cells Compared with the BRAF Inhibitor PLX4720 and Shown by Detailed Pathway Analysis","volume":"1867","author":"Koumaki","year":"2021","journal-title":"Biochim. Et Biophys. Acta (BBA)-Mol. Basis Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"TPS2091","DOI":"10.1200\/JCO.2025.43.16_suppl.TPS2091","article-title":"FORTE: A Phase 2 Master Protocol Assessing Plixorafenib for BRAF-Altered Cancers","volume":"43","author":"Schreck","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5606","DOI":"10.1158\/1538-7445.AM2025-5606","article-title":"Abstract 5606: The Novel Brain-Penetrant Paradox Breaker BRAF Inhibitor RG6344 Manifests Exceptional Activity in BRAF Mutant Colorectal Cancers","volume":"85","author":"Renner","year":"2025","journal-title":"Cancer Res."},{"key":"ref_85","unstructured":"(2026, February 28). Study Details. NCT06411600. Combination Therapy for BRAF-V600E Metastatic CRCm. ClinicalTrials.Gov, Available online: https:\/\/clinicaltrials.gov\/study\/NCT06411600#study-plan."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"21949","DOI":"10.1038\/srep21949","article-title":"The Structural Basis of Oncogenic Mutations G12, G13 and Q61 in Small GTPase K-Ras4B","volume":"6","author":"Lu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1158\/2159-8290.CD-23-1138","article-title":"Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers","volume":"14","author":"Rubinson","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1158\/2159-8290.CD-21-1331","article-title":"Expanding the Reach of Precision Oncology by Drugging All KRAS Mutants","volume":"12","author":"Hofmann","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Patelli, G., Tosi, F., Amatu, A., Mauri, G., Curaba, A., Patan\u00e8, D.A., Pani, A., Scaglione, F., Siena, S., and Sartore-Bianchi, A. (2021). Strategies to Tackle RAS-Mutated Metastatic Colorectal Cancer. ESMO Open, 6.","DOI":"10.1016\/j.esmoop.2021.100156"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"100567","DOI":"10.1016\/j.esmoop.2022.100567","article-title":"Clinical Efficacy of Sequential Treatments in KRASG12C-Mutant Metastatic Colorectal Cancer: Findings from a Real-Life Multicenter Italian Study (CRC-KR GOIM)","volume":"7","author":"Ciardiello","year":"2022","journal-title":"ESMO Open"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1093\/oncolo\/oyac077","article-title":"Real-World Study of Characteristics and Treatment Outcomes Among Patients with KRAS p.G12C-Mutated or Other KRAS Mutated Metastatic Colorectal Cancer","volume":"27","author":"Fakih","year":"2022","journal-title":"Oncologist"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/s41591-023-02240-8","article-title":"Codon-Specific KRAS Mutations Predict Survival Benefit of Trifluridine\/Tipiracil in Metastatic Colorectal Cancer","volume":"29","author":"Ma","year":"2023","journal-title":"Nat. Med."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Ros, J., Vaghi, C., Baraibar, I., Saoudi Gonz\u00e1lez, N., Rodr\u00edguez-Castells, M., Garc\u00eda, A., Alcaraz, A., Salva, F., Tabernero, J., and Elez, E. (2024). Targeting KRAS G12C Mutation in Colorectal Cancer, A Review: New Arrows in the Quiver. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25063304"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1200\/JCO.23.00434","article-title":"Adagrasib in Advanced Solid Tumors Harboring a KRASG12C Mutation","volume":"41","author":"Yaeger","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1056\/NEJMoa2204619","article-title":"Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRASG12C Mutation","volume":"387","author":"Riely","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2371","DOI":"10.1056\/NEJMoa2103695","article-title":"Sotorasib for Lung Cancers with KRAS p.G12C Mutation","volume":"384","author":"Skoulidis","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1056\/NEJMoa2212419","article-title":"Adagrasib with or Without Cetuximab in Colorectal Cancer with Mutated KRAS G12C","volume":"388","author":"Yaeger","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMoa1917239","article-title":"KRASG12C Inhibition with Sotorasib in Advanced Solid Tumors","volume":"383","author":"Hong","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1158\/1078-0432.CCR-19-3523","article-title":"Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition","volume":"26","author":"Ryan","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/s41591-023-02717-6","article-title":"Sotorasib with Panitumumab in Chemotherapy-Refractory KRASG12C-Mutated Colorectal Cancer: A Phase 1b Trial","volume":"30","author":"Kuboki","year":"2024","journal-title":"Nat. Med."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Saoudi Gonzalez, N., Patelli, G., and Crisafulli, G. (2025). Clinical Actionability of Genes in Gastrointestinal Tumors. Genes, 16.","DOI":"10.3390\/genes16101130"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"S1391","DOI":"10.1016\/j.annonc.2022.08.020","article-title":"LBA24 KRYSTAL-1: Updated Efficacy and Safety of Adagrasib (MRTX849) with or Without Cetuximab in Patients with Advanced Colorectal Cancer (CRC) Harboring a KRASG12C Mutation","volume":"33","author":"Klempner","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41591-023-02696-8","article-title":"Divarasib plus Cetuximab in KRAS G12C-Positive Colorectal Cancer: A Phase 1b Trial","volume":"30","author":"Desai","year":"2024","journal-title":"Nat. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1158\/2159-8290.CD-20-0187","article-title":"EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer","volume":"10","author":"Amodio","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1056\/NEJMoa2308795","article-title":"Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C","volume":"389","author":"Fakih","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","article-title":"Acquired Resistance to KRAS G12C Inhibition in Cancer","volume":"384","author":"Awad","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1200\/JCO.2025.43.16_suppl.3540","article-title":"Biomarkers of Emergent Resistance to Sotorasib plus Panitumumab in KRAS G12C-Mutated Metastatic Colorectal Cancer (MCRC) from the Randomized, Phase 3 CodeBreaK 300 Study","volume":"43","author":"Salvatore","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1158\/2159-8290.CD-19-1167","article-title":"The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients","volume":"10","author":"Hallin","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"CT242","DOI":"10.1158\/1538-7445.AM2022-CT242","article-title":"Abstract CT242: KRYSTAL-16: A Phase I\/Ib Trial of Adagrasib (MRTX849) in Combination with Palbociclib in Patients with Advanced Solid Tumors with KRASG12C Mutation","volume":"82","author":"Sommerhalder","year":"2022","journal-title":"Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41698-025-01166-3","article-title":"KRAS-Targeted Therapies in Colorectal Cancer: A Systematic Analysis of Mutations, Inhibitors, and Clinical Trials","volume":"9","author":"Mulet","year":"2025","journal-title":"npj Precis. Oncol."},{"key":"ref_111","first-page":"TPS326","article-title":"A Phase 3 Study of First-Line Sotorasib, Panitumumab, and FOLFIRI versus FOLFIRI with or Without Bevacizumab-Awwb for Patients with KRAS G12C\u2013Mutated Metastatic Colorectal Cancer (CodeBreaK 301)","volume":"43","author":"Kim","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"TPS267","DOI":"10.1200\/JCO.2026.44.2_suppl.TPS267","article-title":"KANDLELIT-012: Phase 3 Study of MK-1084 (a KRAS G12C Inhibitor) plus Cetuximab and MFOLFOX6 with or Without Bevacizumab for KRAS G12C-Mutant Colorectal Cancer","volume":"44","author":"Kawazoe","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/s41575-019-0245-4","article-title":"Role of Oncogenic KRAS in the Diagnosis, Prognosis and Treatment of Pancreatic Cancer","volume":"17","author":"Buscail","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41573-020-0068-6","article-title":"RAS-Targeted Therapies: Is the Undruggable Drugged?","volume":"19","author":"Moore","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.prp.2009.07.010","article-title":"Frequency and Type of KRAS Mutations in Routine Diagnostic Analysis of Metastatic Colorectal Cancer","volume":"205","author":"Neumann","year":"2009","journal-title":"Pathol. Res. Pract."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1200\/JCO.2025.43.4_suppl.724","article-title":"Preliminary Safety, Antitumor Activity, and Circulating Tumor DNA (CtDNA) Changes with RMC-9805, an Oral, RAS(ON) G12D-Selective Tri-Complex Inhibitor in Patients with KRAS G12D Pancreatic Ductal Adenocarcinoma (PDAC) from a Phase 1 Study in Advanced Solid Tumors","volume":"43","author":"Spira","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1158\/1078-0432.CCR-23-2098","article-title":"A Small Molecule with Big Impact: MRTX1133 Targets the KRASG12D Mutation in Pancreatic Cancer","volume":"30","author":"Wei","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1038\/s41591-022-02007-7","article-title":"Anti-Tumor Efficacy of a Potent and Selective Non-Covalent KRASG12D Inhibitor","volume":"28","author":"Hallin","year":"2022","journal-title":"Nat. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1038\/s43018-023-00615-x","article-title":"A Single Inhibitor for All KRAS Mutations","volume":"4","author":"Corcoran","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Lito, P., Solomon, M., Li, L.-S., and Hansen, R. (2026, February 15). Combination of RAS(ON) G12C-Selective and Multi-Selective Tri-Complex Inhibitors Overcomes Resistance and Prolongs Durability in Preclinical Models of KRAS G12C NSCLC. Abstract nr. 5512. Presented at: The American Association for Cancer Research (AACR) Annual Meeting. Available online: https:\/\/www.researchgate.net\/publication\/390993056_Abstract_5512_Combining_RASON_G12C-selective_and_RASON_multi-selective_inhibitors_overcomes_sotorasib_resistance_driven_by_KRASG12C_amplification_or_NRASG13R_mutation.","DOI":"10.1158\/1538-7445.AM2025-5512"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41586-024-07205-6","article-title":"Concurrent Inhibition of Oncogenic and Wild-Type RAS-GTP for Cancer Therapy","volume":"629","author":"Holderfield","year":"2024","journal-title":"Nature"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"S458","DOI":"10.1016\/j.annonc.2023.09.1838","article-title":"652O Preliminary Clinical Activity of RMC-6236, a First-in-Class, RAS-Selective, Tri-Complex RAS-MULTI(ON) Inhibitor in Patients with KRAS Mutant Pancreatic Ductal Adenocarcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC)","volume":"34","author":"Arbour","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41586-023-06123-3","article-title":"Pan-KRAS Inhibitor Disables Oncogenic Signalling and Tumour Growth","volume":"619","author":"Kim","year":"2023","journal-title":"Nature"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1016\/j.ccell.2025.07.006","article-title":"A Pan-KRAS Inhibitor and Its Derived Degrader Elicit Multifaceted Anti-Tumor Efficacy in KRAS-Driven Cancers","volume":"43","author":"Feng","year":"2025","journal-title":"Cancer Cell"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1158\/2159-8290.CD-11-0261","article-title":"HER2 Signaling and Resistance to the Anti-EGFR Monoclonal Antibody Cetuximab: A Further Step toward Personalized Medicine for Patients with Colorectal Cancer","volume":"1","author":"Ciardiello","year":"2011","journal-title":"Cancer Discov."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1093\/annonc\/mdy100","article-title":"Targeting the Human Epidermal Growth Factor Receptor 2 (HER2) Oncogene in Colorectal Cancer","volume":"29","author":"Siena","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"10213","DOI":"10.1038\/s41467-024-53223-3","article-title":"HER2-Related Biomarkers Predict Clinical Outcomes with Trastuzumab Deruxtecan Treatment in Patients with HER2-Expressing Metastatic Colorectal Cancer: Biomarker Analyses of DESTINY-CRC01","volume":"15","author":"Siena","year":"2024","journal-title":"Nature Commun."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"4619","DOI":"10.3748\/wjg.v22.i19.4619","article-title":"HER2 Testing in Gastric Cancer: An Update","volume":"22","author":"Lucas","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1016\/S1470-2045(16)00150-9","article-title":"Dual-Targeted Therapy with Trastuzumab and Lapatinib in Treatment-Refractory, KRAS Codon 12\/13 Wild-Type, HER2-Positive Metastatic Colorectal Cancer (HERACLES): A Proof-of-Concept, Multicentre, Open-Label, Phase 2 Trial","volume":"17","author":"Trusolino","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/S1470-2045(21)00086-3","article-title":"Trastuzumab Deruxtecan (DS-8201) in Patients with HER2-Expressing Metastatic Colorectal Cancer (DESTINY-CRC01): A Multicentre, Open-Label, Phase 2 Trial","volume":"22","author":"Siena","year":"2021","journal-title":"Lancet Oncol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s40265-025-02253-2","article-title":"Targeting HER2 in Metastatic Colorectal Cancer: Current Therapies, Biomarker Refinement, and Emerging Strategies","volume":"86","author":"Vaghi","year":"2025","journal-title":"Drugs"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S1470-2045(24)00380-2","article-title":"Trastuzumab Deruxtecan in Patients with HER2-Positive Advanced Colorectal Cancer (DESTINY-CRC02): Primary Results from a Multicentre, Randomised, Phase 2 Trial","volume":"25","author":"Raghav","year":"2024","journal-title":"Lancet Oncol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1200\/JCO.2025.43.4_suppl.277","article-title":"Acquired Gene Alterations Potentially Related to Resistance to Anti-HER2 Therapy in HER2-Positive Metastatic Colorectal Cancer (MCRC)","volume":"43","author":"Hoyek","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Rha, S.Y., Lee, K.-W., Lee, S., Kang, Y.-K., Chandana, S., Escalante, A., Xie, C., Garfin, P., and Iqbal, S. (2024, January 13\u201317). 516MO-Zanidatamab + Chemotherapy in First-Line Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Advanced\/Metastatic Colorectal Cancer (CRC) Part 1 of a Phase 2 Study. Proceedings of the ESMO Congress 2024, Barcelona, Spain.","DOI":"10.1016\/j.annonc.2024.08.585"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"TPS261","DOI":"10.1200\/JCO.2023.41.4_suppl.TPS261","article-title":"MOUNTAINEER-03: Phase 3 Study of Tucatinib, Trastuzumab, and MFOLFOX6 as First-Line Treatment in HER2+ Metastatic Colorectal Cancer\u2014Trial in Progress","volume":"41","author":"Tabernero","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1200\/JCO.20.01994","article-title":"Randomized Trial of Irinotecan and Cetuximab with or Without Vemurafenib in BRAF-Mutant Metastatic Colorectal Cancer (SWOG S1406)","volume":"39","author":"Kopetz","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"S489","DOI":"10.1016\/j.annonc.2025.08.1320","article-title":"746P A 2-Year Follow-up of Zanidatamab (Zani) + MFOLFOX6 \u00b1 Bevacizumab (Bev) in First-Line (1L) Treatment of Patients (Pts) with Human Epidermal Growth Factor Receptor 2-Positive (HER2+) Advanced\/Metastatic Colorectal Cancer (MCRC)","volume":"36","author":"Rha","year":"2025","journal-title":"Ann. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1038\/s41568-024-00737-z","article-title":"Cancer Drug-Tolerant Persister Cells: From Biological Questions to Clinical Opportunities","volume":"24","author":"Russo","year":"2024","journal-title":"Nat. Rev. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41540-017-0016-1","article-title":"Clinical Responses to ERK Inhibition in BRAFV600E-Mutant Colorectal Cancer Predicted Using a Computational Model","volume":"3","author":"Kirouac","year":"2017","journal-title":"NPJ Syst. Biol. Appl."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/460\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T10:43:05Z","timestamp":1776249785000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/460"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":139,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040460"],"URL":"https:\/\/doi.org\/10.3390\/genes17040460","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]}}}