{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:41:35Z","timestamp":1773769295678,"version":"3.50.1"},"reference-count":105,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although rare in non-small cell lung cancer (NSCLC), BRAF mutations present considerable therapeutic challenges. While the use of BRAF and MEK inhibitor combinations has significantly improved survival outcomes in patients with BRAF V600E mutations, no targeted therapies are currently available for class II and III mutations, leaving the optimal treatment strategy and prognosis for these patients uncertain. Additionally, despite immunotherapy typically showing limited benefit in patients with other activating genomic alterations, it appears to deliver comparable efficacy in BRAF-mutated NSCLC, emerging as a potentially viable treatment option, particularly in patients with a history of smoking. However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.<\/jats:p>","DOI":"10.3390\/ijms252312972","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T04:01:29Z","timestamp":1733198489000},"page":"12972","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Navigating Therapeutic Challenges in BRAF-Mutated NSCLC: Non-V600 Mutations, Immunotherapy, and Overcoming Resistance"],"prefix":"10.3390","volume":"25","author":[{"given":"Martina","family":"Bortolot","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"},{"name":"Department of Medicine (DME), University of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2490-0556","authenticated-orcid":false,"given":"Sara","family":"Torresan","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"},{"name":"Department of Medicine (DME), University of Udine, 33100 Udine, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisa","family":"De Carlo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8045-6838","authenticated-orcid":false,"given":"Elisa","family":"Bertoli","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0475-7399","authenticated-orcid":false,"given":"Brigida","family":"Stanzione","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1763-0335","authenticated-orcid":false,"given":"Alessandro","family":"Del Conte","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Spina","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1020-2338","authenticated-orcid":false,"given":"Alessandra","family":"Bearz","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1097\/JTO.0000000000000644","article-title":"BRAF Alterations as Therapeutic Targets in Non\u2013Small-Cell Lung Cancer","volume":"10","author":"Bouchaab","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.ctrv.2018.04.006","article-title":"BRAF in non-small cell lung cancer (NSCLC): Pickaxing another brick in the wall","volume":"66","author":"Leonetti","year":"2018","journal-title":"Cancer Treat. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nature23291","article-title":"Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS","volume":"548","author":"Yao","year":"2017","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1158\/2159-8290.CD-18-1321","article-title":"Targeting alterations in the RAF-MEK pathway","volume":"9","author":"Yaeger","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1016\/S0092-8674(04)00215-6","article-title":"Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF","volume":"116","author":"Wan","year":"2004","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"\u015amiech, M., Leszczy\u0144ski, P., Kono, H., Wardell, C., and Taniguchi, H. (2020). Emerging BRAF Mutations in Cancer Progression and Their Possible Effects on Transcriptional Networks. Genes, 11.","DOI":"10.3390\/genes11111342"},{"key":"ref_7","unstructured":"(2024, September 11). Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N. Engl. J. Med., Available online: https:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa1904059."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1056\/NEJMoa1408868","article-title":"Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma","volume":"371","author":"Larkin","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_9","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_10","first-page":"1451","article-title":"Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort","volume":"10","author":"Gautschi","year":"2015","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/S1470-2045(16)00077-2","article-title":"Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: A single-arm, multicentre, open-label, phase 2 trial","volume":"17","author":"Planchard","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/S1470-2045(16)30146-2","article-title":"An open-label phase 2 trial of dabrafenib plus trametinib in patients with previously treated BRAF V600E\u2013mutant metastatic non-small cell lung cancer","volume":"17","author":"Planchard","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/S1470-2045(17)30679-4","article-title":"Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: An open-label, phase 2 trial","volume":"18","author":"Planchard","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.annonc.2022.12.009","article-title":"Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up\u2606","volume":"34","author":"Hendriks","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"National Comprehensive Cancer Network (NCCN) (2015). NCCN clinical practice guidelines in oncology. Thorac. Surg. Clin., 25, 185\u2013197.","DOI":"10.1016\/j.thorsurg.2014.12.003"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S1246","DOI":"10.1016\/j.annonc.2024.08.2298","article-title":"LBA56\u2014Updated efficacy and safety from the phase II PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC)","volume":"35","author":"Riely","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1093\/annonc\/mdz141","article-title":"EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer","volume":"30","author":"Hastings","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_18","first-page":"1611","article-title":"Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations","volume":"15","author":"Negrao","year":"2020","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S455","DOI":"10.1016\/j.jtho.2019.08.942","article-title":"P1.04-39 Molecular Characteristics, Immunophenotype, and Immune Checkpoint Inhibitor Response in BRAF Non-V600 Mutant Lung Cancers","volume":"14","author":"Offin","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.lungcan.2015.11.006","article-title":"Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations","volume":"91","author":"Tissot","year":"2016","journal-title":"Lung Cancer Amst. Neth."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1158\/1078-0432.CCR-18-2062","article-title":"Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer","volume":"25","author":"Martinez","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_22","first-page":"211","article-title":"BRAF mutations and BRAF mutation functional class have no negative impact on the clinical outcome of advanced NSCLC and associate with susceptibility to immunotherapy","volume":"149","author":"Wiesweg","year":"2021","journal-title":"Eur. J. Cancer Oxf. Engl. 1990"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Perrone, F., Mazzaschi, G., Minari, R., Verz\u00e8, M., Azzoni, C., Bottarelli, L., Nizzoli, R., Pluchino, M., Altimari, A., and Gruppioni, E. (2022). Multicenter Observational Study on Metastatic Non-Small Cell Lung Cancer Harboring BRAF Mutations: Focus on Clinical Characteristics and Treatment Outcome of V600E and Non-V600E Subgroups. Cancers, 14.","DOI":"10.3390\/cancers14082019"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4532","DOI":"10.1158\/1078-0432.CCR-13-0657","article-title":"Clinical, Pathologic, and Biologic Features Associated with BRAF Mutations in Non\u2013Small Cell Lung Cancer","volume":"19","author":"Cardarella","year":"2013","journal-title":"Clin Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1016\/j.jtho.2023.07.024","article-title":"Clinicogenomic Features and Targetable Mutations in NSCLCs Harboring BRAF Non-V600E Mutations: A Multi-Institutional Genomic Screening Study (LC-SCRUM-Asia)","volume":"18","author":"Sakai","year":"2023","journal-title":"J. Thorac. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3700","DOI":"10.1200\/JCO.23.00774","article-title":"Phase II, Open-Label Study of Encorafenib Plus Binimetinib in Patients with BRAFV600-Mutant Metastatic Non\u2013Small-Cell Lung Cancer","volume":"41","author":"Riely","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/j.lungcan.2013.08.012","article-title":"Lung adenocarcinoma with BRAF G469L mutation refractory to vemurafenib","volume":"82","author":"Gautschi","year":"2013","journal-title":"Lung Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e174","DOI":"10.1016\/j.jtho.2020.07.007","article-title":"Durable Response to Dabrafenib Combined with Trametinib in a Patient with NSCLC Harboring a BRAF G469A Mutation","volume":"15","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e219","DOI":"10.1016\/j.cllc.2019.02.022","article-title":"Clinical Benefit From BRAF\/MEK Inhibition in a Double Non-V600E BRAF Mutant Lung Adenocarcinoma: A Case Report","volume":"20","author":"Reyes","year":"2019","journal-title":"Clin. Lung Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1097\/CAD.0000000000000277","article-title":"A significant response to sorafenib in a woman with advanced lung adenocarcinoma and a BRAF non-V600 mutation","volume":"26","author":"Sereno","year":"2015","journal-title":"Anti-Cancer Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"196","DOI":"10.3390\/curroncol28010021","article-title":"A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker","volume":"28","author":"Turshudzhyan","year":"2020","journal-title":"Curr. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1007\/s00432-024-05675-9","article-title":"BRAF\/MEK-targeted therapy in BRAF ex15 p.T599dup mutation-driven NSCLC: A case report","volume":"150","author":"Jiang","year":"2024","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lazar, R., Fischbach, C., Schott, R., and Somme, L. (2024). Outcomes of non-small cell lung cancer patients with non-V600E BRAF mutations: A series of case reports and literature review. Front. Oncol., 14.","DOI":"10.3389\/fonc.2024.1307882"},{"key":"ref_34","first-page":"e11224","article-title":"Immunotherapy Benefit in a Patient with Non-Small Cell Lung Cancer and a Rare BRAF Mutation","volume":"12","author":"Rittberg","year":"2020","journal-title":"Cureus"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e01155","DOI":"10.1002\/rcr2.1155","article-title":"PD-L1-negative non-small cell lung cancer harbouring a rare BRAF mutation with successful treatment of first-line pembrolizumab plus chemotherapy: A case report and review the literature","volume":"11","author":"Do","year":"2023","journal-title":"Respirol. Case Rep."},{"key":"ref_36","first-page":"100202","article-title":"Durable Response to Combined Dabrafenib and Trametinib in a Patient with BRAF K601E Mutation-Positive Lung Adenocarcinoma: A Case Report","volume":"2","author":"Su","year":"2021","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Gardini, A.C., Chiadini, E., Faloppi, L., Marisi, G., Delmonte, A., Scartozzi, M., Loretelli, C., Lucchesi, A., Oboldi, D., and Dubini, A. (2016). Efficacy of sorafenib in BRAF-mutated non-small-cell lung cancer (NSCLC) and no response in synchronous BRAF wild type-hepatocellular carcinoma: A case report. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2463-2"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1200\/PO.20.00187","article-title":"Targeted Therapy in BRAF p.K601E-Driven NSCLC: Case Report and Literature Review","volume":"4","author":"Saalfeld","year":"2020","journal-title":"JCO Precis Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"19","DOI":"10.21037\/pcm-21-24","article-title":"Ineffective target therapy in non-small cell lung cancer harboring BRAF G466R mutation: A case report and biological rationale","volume":"5","author":"Citarella","year":"2022","journal-title":"Precis. Cancer Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1200\/JCO.2024.42.16_suppl.3104","article-title":"Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations (mts): Final results of the investigator-initiated phase II BEAVER trial","volume":"42","author":"Rose","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.annonc.2019.10.022","article-title":"Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations","volume":"31","author":"Mazieres","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e2200107","DOI":"10.1200\/PO.22.00107","article-title":"Clinical Activity of Mitogen-Activated Protein Kinase\u2013Targeted Therapies in Patients with Non\u2013V600 BRAF-Mutant Tumors","volume":"6","author":"Dankner","year":"2022","journal-title":"JCO Precis. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.cllc.2019.03.007","article-title":"Efficacy and Safety of BRAF Inhibitors With or Without MEK Inhibitors in BRAF-Mutant Advanced Non\u2013Small-Cell Lung Cancer: Findings From a Real-Life Cohort","volume":"20","author":"Dudnik","year":"2019","journal-title":"Clin. Lung Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"60094","DOI":"10.18632\/oncotarget.11635","article-title":"Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of Trametinib and Dabrafenib","volume":"8","author":"Noeparast","year":"2016","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S491","DOI":"10.1016\/j.annonc.2024.08.680","article-title":"613MO A phase I clinical trial evaluating exarafenib, a selective pan-RAF inhibitor in combination with binimetinib in NRAS-mutant (NRASMut) melanoma (Mel) & BRAF-altered solid tumors","volume":"35","author":"Cassier","year":"2024","journal-title":"Ann. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"CT033","DOI":"10.1158\/1538-7445.AM2023-CT033","article-title":"Abstract CT033: Safety, pharmacokinetics, and antitumor activity findings from a phase 1b, open-label, dose-escalation and expansion study investigating RAF dimer inhibitor lifirafenib in combination with MEK inhibitor mirdametinib in patients with advanced or refractory solid tumors","volume":"83","author":"Solomon","year":"2023","journal-title":"Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"CT031","DOI":"10.1158\/1538-7445.AM2023-CT031","article-title":"Abstract CT031: A first-in-human, phase 1a\/1b, open-label, dose-escalation and expansion study to investigate the safety, pharmacokinetics, and antitumor activity of the RAF dimer in-hibitor BGB-3245 in patients with advanced or refractory tumors","volume":"83","author":"Schram","year":"2023","journal-title":"Cancer Res."},{"key":"ref_48","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_49","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1158\/2159-8290.CD-17-1119","article-title":"First-in-Class ERK1\/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study","volume":"8","author":"Sullivan","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"107964","DOI":"10.1016\/j.lungcan.2024.107964","article-title":"A phase Ib study of the combination of naporafenib with rineterkib or tra-metinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer","volume":"197","author":"Planchard","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Adamopoulos, C., Papavassiliou, K.A., Poulikakos, P.I., and Papavassiliou, A.G. (2024). RAF and MEK Inhibitors in Non-Small Cell Lung Cancer. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25094633"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"TPS3180","DOI":"10.1200\/JCO.2024.42.16_suppl.TPS3180","article-title":"A phase 1, open-label, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of PF-07799544 (ARRY-134) as a single agent and in combination with PF-07799933 BRAF dimer inhibitor, in participants 16 years and older with advanced solid tumors","volume":"42","author":"Beck","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/s41556-018-0169-1","article-title":"RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers","volume":"20","author":"Nichols","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/annonc\/mdz167","article-title":"Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry","volume":"30","author":"Mazieres","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.jtho.2018.04.024","article-title":"BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors","volume":"13","author":"Dudnik","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e57","DOI":"10.1016\/j.jtho.2018.11.036","article-title":"BRAF Mutant NSCLC and Immune Checkpoint Inhibitors: Results From a Real-World Experience","volume":"14","author":"Rihawi","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_57","first-page":"100006","article-title":"Patients with BRAF-Mutant NSCLC May Not Benefit From Immune Checkpoint In-hibitors: A Population-Based Study","volume":"1","author":"Zhang","year":"2020","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_58","first-page":"628","article-title":"Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients with Advanced NSCLC with BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018","volume":"15","author":"Guisier","year":"2020","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"861","DOI":"10.21037\/tlcr-24-116","article-title":"Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: A multicenter real-world analysis","volume":"13","author":"Tian","year":"2024","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e002891","DOI":"10.1136\/jitc-2021-002891","article-title":"Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer","volume":"9","author":"Negrao","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"107865","DOI":"10.1016\/j.lungcan.2024.107865","article-title":"BRAF mutational status is associated with survival outcomes in locally advanced resectable and metastatic NSCLC","volume":"194","author":"Provencio","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1056\/NEJMoa2215530","article-title":"Perioperative Nivolumab and Chemotherapy in Stage III Non\u2013Small-Cell Lung Cancer","volume":"389","author":"Provencio","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1200\/JCO.2010.33.1280","article-title":"Clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations","volume":"29","author":"Paik","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.ejca.2022.02.014","article-title":"Durvalumab consolidation in patients with un-resectable stage III non-small cell lung cancer with driver genomic alterations","volume":"167","author":"Riudavets","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s12943-020-1144-6","article-title":"Predictive biomarkers and mechanisms underlying resistance to PD1\/PD-L1 blockade cancer immunotherapy","volume":"19","author":"Ren","year":"2020","journal-title":"Mol. Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1158\/2159-8290.CD-20-0522","article-title":"Tumor Mutational Burden (TMB) as a Predictive Biomarker in Solid Tumors","volume":"10","author":"Sha","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"107787","DOI":"10.1016\/j.lungcan.2024.107787","article-title":"The biomarkers ATLAS: An audit on 1100 non-small cell lung cancer from an Italian knowledge-based database","volume":"191","author":"Malapelle","year":"2024","journal-title":"Lung Cancer"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1007\/s00262-020-02714-5","article-title":"Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer","volume":"70","author":"Adderley","year":"2020","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.immuni.2016.01.024","article-title":"MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade","volume":"44","author":"Ebert","year":"2016","journal-title":"Immunity"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1158\/1078-0432.CCR-11-2479","article-title":"Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma","volume":"18","author":"Wilmott","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4155","DOI":"10.1158\/1538-7445.AM2023-4155","article-title":"Abstract 4155: The RAF\/MEK clamp avutometinib (VS-6766) induces an immu-nogenic tumor microenvironment and potentiates the efficacy of anti-PD-1","volume":"83","author":"Coma","year":"2023","journal-title":"Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Welti, M., Dimitriou, F., Gutzmer, R., and Dummer, R. (2022). Triple Combination of Immune Checkpoint Inhibitors and BRAF\/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives. Cancers, 14.","DOI":"10.3390\/cancers14225489"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1093\/annonc\/mdz113","article-title":"Phase Ib study of atezolizumab combined with cobimetinib in patients with solid tumors","volume":"30","author":"Hellmann","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1158\/2159-8290.CD-13-0617","article-title":"The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma","volume":"4","author":"Wagle","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1038\/nature09626","article-title":"Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation","volume":"468","author":"Nazarian","year":"2010","journal-title":"Nature"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1097\/JTO.0b013e31828bb1b3","article-title":"Molecular Characterization of Acquired Resistance to the BRAF Inhibitor Dabrafenib in a Patient with BRAF-Mutant Non\u2013Small-Cell Lung Cancer","volume":"8","author":"Rudin","year":"2013","journal-title":"J. Thorac. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e249","DOI":"10.1016\/j.jtho.2018.07.103","article-title":"KRAS mutation as a resistance mechanism to BRAF\/MEK inhibition in NSCLC","volume":"13","author":"Niemantsverdriet","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e131","DOI":"10.1016\/j.jtho.2018.03.026","article-title":"An Acquired NRAS Q61K Mutation in BRAF V600E-Mutant Lung Adenocarcinoma Resistant to Dabrafenib Plus Trametinib","volume":"13","author":"Abravanel","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.ejca.2020.03.025","article-title":"Molecular mechanisms of resistance to BRAF and MEK inhibitors in BRAFV600E non\u2013small cell lung cancer","volume":"132","author":"Facchinetti","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1158\/2159-8290.CD-13-0642","article-title":"Acquired resistance and clonal evolution in Melanoma during BRAF inhibitor therapy","volume":"4","author":"Shi","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1158\/2159-8290.CD-13-0279","article-title":"A Novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition","volume":"4","author":"Shi","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"7202","DOI":"10.1158\/1078-0432.CCR-18-2779","article-title":"Adaptive Resistance to Dual BRAF\/MEK Inhibition in BRAF-Driven Tumors through Autocrine FGFR Pathway Activation","volume":"25","author":"Wang","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/nature18600","article-title":"A combinatorial strategy for treating KRAS-mutant lung cancer","volume":"534","author":"Manchado","year":"2016","journal-title":"Nature"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/ng.3218","article-title":"The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies","volume":"47","author":"Lin","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.21037\/tlcr-21-415","article-title":"Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer","volume":"10","author":"Hirai","year":"2021","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1097\/CAD.0000000000001623","article-title":"MET alterations as resistance mechanisms of dabrafenib-trametinib in BRAF p.V600E mutated non-small cell lung cancer patient","volume":"35","author":"Pluchino","year":"2024","journal-title":"Anti-Cancer Drugs"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"3901","DOI":"10.1038\/ncomms4901","article-title":"Mixed lineage kinases activate MEK inde-pendently of RAF to mediate resistance to RAF inhibitors","volume":"5","author":"Marusiak","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"4868","DOI":"10.1158\/1078-0432.CCR-13-0827","article-title":"Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436)","volume":"19","author":"Nathanson","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/nature11183","article-title":"Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion","volume":"487","author":"Straussman","year":"2012","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1158\/2159-8290.CD-13-1007","article-title":"The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNF\u03b1","volume":"4","author":"Smith","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1158\/1078-0432.CCR-14-1554","article-title":"BRAF Inhibition Stimulates Melanoma-Associated Macrophages to Drive Tumor Growth","volume":"21","author":"Wang","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/s41698-024-00684-w","article-title":"Efficacy of PARP inhibitor therapy after targeted BRAF\/MEK failure in advanced melanoma","volume":"8","author":"Phillipps","year":"2024","journal-title":"npj Precis. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1038\/nm.4369","article-title":"An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer","volume":"23","author":"Xue","year":"2017","journal-title":"Nat. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1158\/1535-7163.MCT-19-0183","article-title":"ERK Inhibitor LY3214996 Targets ERK Pathway\u2013Driven Cancers: A Therapeutic Approach Toward Precision Medicine","volume":"19","author":"Bhagwat","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e15088","DOI":"10.1200\/JCO.2023.41.16_suppl.e15088","article-title":"A phase 2 basket trial of an ERK1\/2 inhibitor (LY3214996) in combination with abemaciclib for patients whose tumors harbor pathogenic alterations in BRAF, RAF1, MAP2K1\/2 ERK1\/2, and NF1","volume":"41","author":"Taza","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s12094-021-02688-5","article-title":"Cyclin-dependent kinase (CDK) inhibitors in solid tumors: A review of clinical trials","volume":"24","author":"Panagiotou","year":"2021","journal-title":"Clin. Transl. Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1200\/JCO.2016.34.15_suppl.2517","article-title":"Co-targeting BRAF with mTOR inhibition in solid tumors harboring BRAF mutations: A phase I study","volume":"34","author":"Sen","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1158\/2159-8290.CD-23-0361","article-title":"SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy","volume":"13","author":"Drilon","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Koumaki, K., Kontogianni, G., Kosmidou, V., Pahitsa, F., Kritsi, E., Zervou, M., Chatziioannou, A., Souliotis, V.L., Papadodima, O., and Pintzas, A. (2021). 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. Biochim. Biophys. Acta Mol. Basis Dis., 1867.","DOI":"10.1016\/j.bbadis.2020.166061"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"13456","DOI":"10.1073\/pnas.1610456113","article-title":"Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer","volume":"113","author":"Okimoto","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"3000","DOI":"10.1200\/JCO.2019.37.15_suppl.3000","article-title":"Belvarafenib, a novel pan-RAF inhibitor, in solid tumor patients harboring BRAF, KRAS, or NRAS mutations: Phase I study","volume":"37","author":"Kim","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_102","first-page":"4609","article-title":"The paradox-breaker BRAF inhibitor plixo-rafenib (PLX8394; FORE8394) synergizes with MEK inhibitors (MEKi) in BRAF V600 and non-V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi","volume":"84","author":"Cohen","year":"2024","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3107","DOI":"10.1200\/JCO.2024.42.16_suppl.3107","article-title":"Interim analysis of ABM-1310, a blood-brain barrier-penetrant BRAF inhibitor, in patients with BRAF V600-mutated solid tumors","volume":"42","author":"Iwamoto","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1158\/1538-7445.AM2023-475","article-title":"Abstract 475: Preclinical development of ABM-168, a novel MEK Inhibitor to treat cancer with brain tumors","volume":"83","author":"Chen","year":"2023","journal-title":"Cancer Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/s41591-020-1060-8","article-title":"Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: A randomized phase 2 trial","volume":"26","author":"Algazi","year":"2020","journal-title":"Nat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12972\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:45:30Z","timestamp":1760114730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/23\/12972"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,3]]},"references-count":105,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252312972"],"URL":"https:\/\/doi.org\/10.3390\/ijms252312972","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,3]]}}}