{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T02:30:44Z","timestamp":1791599444170,"version":"4.3.4"},"reference-count":103,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osimertinib is currently the preferred first-line therapy in patients with non-small cell lung cancer (NSCLC) with common epidermal growth factor receptor (EGFR) mutation and the standard second-line therapy in T790M-positive patients in progression to previous EGFR tyrosine kinase inhibitor. Osimertinib is a highly effective treatment that shows a high response rate and long-lasting disease control. However, a resistance to the treatment inevitably develops among patients. Understanding the secondary mechanisms of resistance and the possible therapeutic options available is crucial to define the best management of patients in progression to osimertinib. We provide a comprehensive review of the emerging molecular resistance mechanism in EGFR-mutated NSCLC pre-treated with osimertinib and its future treatment applications.<\/jats:p>","DOI":"10.3390\/ijms23136936","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T21:31:06Z","timestamp":1655933466000},"page":"6936","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":45,"title":["Acquired Resistance to Osimertinib in EGFR-Mutated Non-Small Cell Lung Cancer: How Do We Overcome It?"],"prefix":"10.3390","volume":"23","author":[{"given":"Elisa","family":"Bertoli","sequence":"first","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"},{"name":"Department of Medicine (DAME), University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"De Carlo","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Del Conte","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0475-7399","authenticated-orcid":false,"given":"Brigida","family":"Stanzione","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4505-9650","authenticated-orcid":false,"given":"Alberto","family":"Revelant","sequence":"additional","affiliation":[{"name":"Dipartimento di Radioterapia, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Fassetta","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Spina","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Bearz","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"ref_1","first-page":"2892","article-title":"EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: A systematic review and global map by ethnicity (mutMapII)","volume":"5","author":"Midha","year":"2015","journal-title":"Am. J. Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"163","DOI":"10.5858\/arpa.2016-0579-CP","article-title":"Worldwide Frequency of Commonly Detected EGFR Mutations","volume":"142","author":"Graham","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1056\/NEJMoa0810699","article-title":"Gefitinib or Carboplatin\u2013Paclitaxel in Pulmonary Adenocarcinoma","volume":"361","author":"Mok","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S1470-2045(11)70393-X","article-title":"Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial","volume":"13","author":"Rosell","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3327","DOI":"10.1200\/JCO.2012.44.2806","article-title":"Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients with Metastatic Lung Adenocarcinoma with EGFR Mutations","volume":"31","author":"Sequist","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"75ra26","DOI":"10.1126\/scitranslmed.3002003","article-title":"Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors","volume":"3","author":"Sequist","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1056\/NEJMoa1612674","article-title":"Osimertinib or Platinum\u2013Pemetrexed in EGFR T790M\u2013Positive Lung Cancer","volume":"376","author":"Mok","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/j.annonc.2020.08.2100","article-title":"Osimertinib versus platinum\u2013pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis","volume":"31","author":"Papadimitrakopoulou","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1073\/pnas.0709662105","article-title":"The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP","volume":"105","author":"Yun","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1158\/2159-8290.CD-14-0337","article-title":"AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer","volume":"4","author":"Cross","year":"2014","journal-title":"Cancer Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1056\/NEJMoa1913662","article-title":"Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC","volume":"382","author":"Ramalingam","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5130","DOI":"10.1158\/1078-0432.CCR-16-0399","article-title":"Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity","volume":"22","author":"Ballard","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"viii741","DOI":"10.1093\/annonc\/mdy424.064","article-title":"Analysis of resistance mechanisms to osimertinib in patients with EGFR T790M advanced NSCLC from the AURA3 study","volume":"29","author":"Papadimitrakopoulou","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"viii740","DOI":"10.1093\/annonc\/mdy424.063","article-title":"Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study","volume":"29","author":"Ramalingam","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6195","DOI":"10.1158\/1078-0432.CCR-18-1542","article-title":"Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EGFR-Mutant NSCLC","volume":"24","author":"Le","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jtho.2019.11.005","article-title":"The Evolving Landscape of Resistance to Osimertinib","volume":"15","author":"Schoenfeld","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1056\/NEJMoa044238","article-title":"EGFR Mutation and Resistance of Non\u2013Small-Cell Lung Cancer to Gefitinib","volume":"352","author":"Kobayashi","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1527","DOI":"10.1001\/jamaoncol.2018.2969","article-title":"Assessment of Resistance Mechanisms and Clinical Implications in Patients with EGFR T790M\u2013Positive Lung Cancer and Acquired Resistance to Osimertinib","volume":"4","author":"Oxnard","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S2213-2600(17)30480-0","article-title":"Outcomes in patients with non-small-cell lung cancer and acquired Thr790Met mutation treated with osimertinib: A genomic study","volume":"6","author":"Lin","year":"2018","journal-title":"Lancet Respir. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.21873\/invivo.12586","article-title":"Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism after Treatment with Osimertinib: A Case Report","volume":"35","author":"Schiappacassi","year":"2021","journal-title":"Vivo"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1038\/s43018-021-00195-8","article-title":"Overcoming therapy resistance in EGFR-mutant lung cancer","volume":"2","author":"Passaro","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/nm.3854","article-title":"Acquired EGFR C797S mutation mediates resistance to AZD9291 in non\u2013small cell lung cancer harboring EGFR T790M","volume":"21","author":"Thress","year":"2015","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e121","DOI":"10.1016\/j.jtho.2016.05.019","article-title":"L718Q Mutation as New Mechanism of Acquired Resistance to AZD9291 in EGFR -Mutated NSCLC","volume":"11","author":"Bersanelli","year":"2016","journal-title":"J. Thorac. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1016\/j.jtho.2019.07.016","article-title":"EGFR-Mutated Lung Cancers Resistant to Osimertinib through EGFR-C797S Respond to 1st Generation Reversible EGFR Inhibitors but Eventually Acquire EGFR-T790M\/C797S in Preclinical Models and Clinical Samples","volume":"14","author":"Rangachari","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1016\/j.jtho.2017.08.006","article-title":"Combination Osimertinib and Gefitinib in C797S and T790M EGFR-Mutated Non\u2013Small Cell Lung Cancer","volume":"12","author":"Arulananda","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1723","DOI":"10.1016\/j.jtho.2017.06.017","article-title":"Lung Adenocarcinoma Harboring EGFR T790M and In Trans C797S Responds to Combination Therapy of First- and Third-Generation EGFR TKIs and Shifts Allelic Configuration at Resistance","volume":"12","author":"Wang","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"S839","DOI":"10.1016\/j.annonc.2020.08.1610","article-title":"1296P BLU-945, a highly potent and selective 4th generation EGFR TKI for the treatment of EGFR T790M\/C797S resistant NSCLC","volume":"31","author":"Schalm","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1158\/2159-8290.CD-18-0903","article-title":"Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor","volume":"9","author":"To","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.canlet.2016.11.008","article-title":"EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance","volume":"385","author":"Wang","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1007\/s43440-020-00131-0","article-title":"Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance","volume":"72","author":"Maity","year":"2020","journal-title":"Pharmacol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"9009","DOI":"10.1200\/JCO.2019.37.15_suppl.9009","article-title":"JNJ-61186372 (JNJ-372), an EGFR-CMet Bispecific Antibody, in EGFR-Driven Advanced Non-Small Cell Lung Cancer (NSCLC)","volume":"37","author":"Haura","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/j.jtho.2020.04.014","article-title":"Effective Treatment of Lung Adenocarcinoma Harboring EGFR-Activating Mutation, T790M, and cis-C797S Triple Mutations by Brigatinib and Cetuximab Combination Therapy","volume":"15","author":"Wang","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"105583","DOI":"10.1016\/j.phrs.2021.105583","article-title":"EGFR mutation mediates resistance to EGFR tyrosine kinase inhibitors in NSCLC: From molecular mechanisms to clinical research","volume":"167","author":"Dong","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"207","DOI":"10.21037\/atm.2019.04.37","article-title":"EGFR L718Q Mutation Occurs without T790M Mutation in a Lung Adenocarcinoma Patient with Acquired Resistance to Osimertinib","volume":"7","author":"Ma","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Liu, J., Jin, B., Su, H., Qu, X., and Liu, Y. (2019). Afatinib helped overcome subsequent resistance to osimertinib in a patient with NSCLC having leptomeningeal metastasis baring acquired EGFR L718Q mutation: A case report. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5915-7"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.2147\/OTT.S188612","article-title":"Newly emergent acquired EGFR exon 18 G724S mutation after resistance of a T790M specific EGFR inhibitor osimertinib in non-small-cell lung cancer: A case report","volume":"12","author":"Zhang","year":"2018","journal-title":"OncoTargets Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4655","DOI":"10.1038\/s41467-018-07078-0","article-title":"Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors","volume":"9","author":"Fassunke","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1016\/j.jtho.2019.06.015","article-title":"A Novel Acquired Exon 20 EGFR M766Q Mutation in Lung Adenocarcinoma Mediates Osimertinib Resistance but is Sensitive to Neratinib and Poziotinib","volume":"14","author":"Castellano","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"11815","DOI":"10.1038\/ncomms11815","article-title":"Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients","volume":"7","author":"Chabon","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.lungcan.2018.02.007","article-title":"Clinical analysis by next-generation sequencing for NSCLC patients with MET amplification resistant to osimertinib","volume":"118","author":"Wang","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"100319","DOI":"10.1016\/j.esmoop.2021.100319","article-title":"Beyond epidermal growth factor receptor: MET amplification as a general resistance driver to targeted therapy in oncogene-driven non-small-cell lung cancer","volume":"6","author":"Coleman","year":"2021","journal-title":"ESMO Open"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1200\/JCO.19.03123","article-title":"Emerging Treatment Paradigms for EGFR-Mutant Lung Cancers Progressing on Osimertinib: A Review","volume":"38","author":"Sequist","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41416-019-0573-8","article-title":"Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer","volume":"121","author":"Leonetti","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1093\/annonc\/mdx396","article-title":"DualMET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC)","volume":"28","author":"Felip","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e169","DOI":"10.1016\/j.jtho.2018.04.007","article-title":"Response to Dual Crizotinib and Osimertinib Treatment in a Lung Cancer Patient with MET Amplification Detected by Liquid Biopsy Who Acquired Secondary Resistance to EGFR Tyrosine Kinase Inhibition","volume":"13","author":"Deng","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2147\/LCTT.S190403","article-title":"Differential response to a combination of full-dose osimertinib and crizotinib in a patient with EGFR-mutant non-small cell lung cancer and emergent MET amplification","volume":"10","author":"Zhu","year":"2019","journal-title":"Lung Cancer Targets Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e232","DOI":"10.1016\/j.jtho.2018.07.012","article-title":"Combination of Crizotinib and Osimertinib or Erlotinib Might Overcome MET-Mediated Resistance to EGFR Tyrosine Kinase Inhibitor in EGFR-Mutated Adenocarcinoma","volume":"13","author":"Dumenil","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S1470-2045(19)30785-5","article-title":"Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: Interim results from a multicentre, open-label, phase 1b study","volume":"21","author":"Sequist","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.1200\/JCO.2018.77.7326","article-title":"Phase Ib\/II Study of Capmatinib (INC280) Plus Gefitinib after Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients with EGFR-Mutated, MET Factor\u2013Dysregulated Non\u2013Small-Cell Lung Cancer","volume":"36","author":"Wu","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1016\/S2213-2600(20)30154-5","article-title":"Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): An open-label, phase 1b\/2, multicentre, randomised trial","volume":"8","author":"Wu","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"9006","DOI":"10.1200\/JCO.2021.39.15_suppl.9006","article-title":"Amivantamab in Combination with Lazertinib for the Treatment of Osimertinib-Relapsed, Chemotherapy-Na\u00efve EGFR Mutant (EGFRm) Non-Small Cell Lung Cancer (NSCLC) and Potential Biomarkers for Response","volume":"39","author":"Bauml","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9006","DOI":"10.1200\/JCO.2022.40.16_suppl.9006","article-title":"Amivantamab and lazertinib in patients with EGFR-mutant non\u2013small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy: Updated results from CHRYSALIS-2","volume":"40","author":"Shu","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9013","DOI":"10.1200\/JCO.2022.40.16_suppl.9013","article-title":"Phase 1\/1b study of telisotuzumab vedotin (Teliso-V) + osimertinib (Osi), after failure on prior Osi, in patients with advanced, c-Met overexpressing, EGFR-mutated non-small cell lung cancer (NSCLC)","volume":"40","author":"Goldman","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1158\/2159-8290.CD-20-0215","article-title":"HER2-Mediated Internalization of Cytotoxic Agents in ERBB2 Amplified or Mutant Lung Cancers","volume":"10","author":"Li","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_55","first-page":"e89","article-title":"Concurrent Acquired BRAF V600E Mutation and MET Amplification as Resistance Mechanism of First-Line Osimertinib Treatment in a Patient with EGFR-Mutated NSCLC","volume":"13","author":"Minari","year":"2018","journal-title":"J. Thoracic Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_56","first-page":"567","article-title":"Acquired BRAF V600E Mutation as Resistant Mechanism after Treatment with Osimertinib","volume":"12","author":"Ho","year":"2017","journal-title":"J. Thoracic Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e390","DOI":"10.1016\/j.cllc.2020.06.008","article-title":"Lung Adenocarcinoma Harboring Concomitant EGFR Mutations and BRAF V600E Responds to a Combination of Osimertinib and Vemurafenib to Overcome Osimertinib Resistance","volume":"22","author":"Xie","year":"2020","journal-title":"Clin. Lung Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2489","DOI":"10.1158\/0008-5472.CAN-14-3167","article-title":"Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models","volume":"75","author":"Eberlein","year":"2015","journal-title":"Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1097\/JTO.0000000000000671","article-title":"Impact of Concurrent PIK3CA Mutations on Response to EGFR Tyrosine Kinase Inhibition in EGFR-Mutant Lung Cancers and on Prognosis in Oncogene-Driven Lung Adenocarcinomas","volume":"10","author":"Eng","year":"2015","journal-title":"J. Thorac. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e114","DOI":"10.1016\/j.jtho.2018.02.005","article-title":"GOPC-ROS1 Rearrangement as an Acquired Resistance Mechanism to Osimertinib and Responding to Crizotinib Combined Treatments in Lung Adenocarcinoma","volume":"13","author":"Zeng","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1158\/2159-8290.CD-18-1022","article-title":"Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion","volume":"8","author":"Piotrowska","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"S230","DOI":"10.1016\/j.jtho.2021.01.150","article-title":"FP14.07 Combination Osimertinib plus Selpercatinib for EGFR-mutant Non-Small Cell Lung Cancer (NSCLC) with Acquired RET fusions","volume":"16","author":"Rotow","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1177\/10600280211036909","article-title":"Combination EGFR and RET Inhibition in Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC","volume":"56","author":"Freydman","year":"2021","journal-title":"Ann. Pharmacother."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.jtho.2018.05.027","article-title":"Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors","volume":"13","author":"Schrock","year":"2018","journal-title":"J. Thorac. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/PO.18.00126","article-title":"Acquired ALK and RET Gene Fusions as Mechanisms of Resistance to Osimertinib in EGFR-Mutant Lung Cancers","volume":"2","author":"Offin","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1111\/1759-7714.13521","article-title":"CDK4\/6 inhibitor palbociclib overcomes acquired resistance to third-generation EGFR inhibitor osimertinib in non-small cell lung cancer (NSCLC)","volume":"11","author":"Qin","year":"2020","journal-title":"Thorac. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"La Monica, S., Fumarola, C., Cretella, D., Bonelli, M., Minari, R., Cavazzoni, A., Digiacomo, G., Galetti, M., Volta, F., and Mancini, M. (2020). Efficacy of the CDK4\/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib. Cancers, 13.","DOI":"10.3390\/cancers13010006"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1158\/1541-7786.MCR-18-0628","article-title":"Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non\u2013Small Cell Lung Cancer Cells","volume":"17","author":"Namba","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1158\/1078-0432.CCR-19-2321","article-title":"ONO-7475, a Novel AXL Inhibitor, Suppresses the Adaptive Resistance to Initial EGFR-TKI Treatment in EGFR-Mutated Non\u2013Small Cell Lung Cancer","volume":"26","author":"Okura","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.lungcan.2020.05.031","article-title":"AXL\/MET dual inhibitor, CB469, has activity in non-small cell lung cancer with acquired resistance to EGFR TKI with AXL or MET activation","volume":"146","author":"Yang","year":"2020","journal-title":"Lung Cancer"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"811247","DOI":"10.3389\/fonc.2022.811247","article-title":"The Development of AXL Inhibitors in Lung Cancer: Recent Progress and Challenges","volume":"12","author":"Sang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1158\/1541-7786.MCR-19-0956","article-title":"IGF2 Autocrine-Mediated IGF1R Activation Is a Clinically Relevant Mechanism of Osimertinib Resistance in Lung Cancer","volume":"18","author":"Manabe","year":"2020","journal-title":"Mol. Cancer Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/1759-7714.13255","article-title":"Activation of insulin-like growth factor-1 receptor confers acquired resistance to osimertinib in non-small cell lung cancer with EGFR T790M mutation","volume":"11","author":"Hayakawa","year":"2019","journal-title":"Thorac. Cancer"},{"key":"ref_74","first-page":"74","article-title":"Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor\u2013Resistant, EGFR-Mutated Non\u2013Small Cell Lung Cancer","volume":"12","author":"Baik","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1200\/JCO.18.01585","article-title":"EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes","volume":"37","author":"Marcoux","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1016\/j.jtho.2019.06.002","article-title":"Concurrent RB1 and TP53 Alterations Define a Subset of EGFR-Mutant Lung Cancers at risk for Histologic Transformation and Inferior Clinical Outcomes","volume":"14","author":"Offin","year":"2019","journal-title":"J. Thorac. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1158\/1078-0432.CCR-19-3563","article-title":"Tumor Analyses Reveal Squamous Transformation and Off-Target Alterations as Early Resistance Mechanisms to First-line Osimertinib in EGFR-Mutant Lung Cancer","volume":"26","author":"Schoenfeld","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.2169\/internalmedicine.3542-19","article-title":"Combined Small and Squamous Transformation in EGFR-mutated Lung Adenocarcinoma","volume":"59","author":"Hakozaki","year":"2020","journal-title":"Intern. Med."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ctrv.2017.07.007","article-title":"Outcome of patients with lung adenocarcinoma with transformation to small-cell lung cancer following tyrosine kinase inhibitors treatment: A systematic review and pooled analysis","volume":"59","author":"Roca","year":"2017","journal-title":"Cancer Treat. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1111\/1759-7714.13906","article-title":"Targeting the EMT transcription factor Snail overcomes resistance to osimertinib in EGFR -mutant non-small cell lung cancer","volume":"12","author":"Qin","year":"2021","journal-title":"Thorac. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/s41388-018-0482-y","article-title":"Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer","volume":"38","author":"Yochum","year":"2018","journal-title":"Oncogene"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e000313","DOI":"10.1136\/esmoopen-2017-000313","article-title":"Updated survival outcomes of NEJ005\/TCOG0902: A randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations","volume":"3","author":"Oizumi","year":"2018","journal-title":"ESMO Open"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1200\/JCO.19.01488","article-title":"Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non\u2013Small-Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor: NEJ009 Study","volume":"38","author":"Hosomi","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1200\/JCO.19.01154","article-title":"Gefitinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer","volume":"38","author":"Noronha","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.cllc.2021.01.010","article-title":"Combining Osimertinib with Chemotherapy in EGFR-Mutant NSCLC at Progression","volume":"22","author":"White","year":"2021","journal-title":"Clin. Lung Cancer"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"100271","DOI":"10.1016\/j.esmoop.2021.100271","article-title":"Osimertinib plus platinum\u2013pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced\/metastatic non-small-cell lung cancer: Safety run-in results from the FLAURA2 study","volume":"6","author":"Planchard","year":"2021","journal-title":"ESMO Open"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2544","DOI":"10.1200\/JCO.2005.02.477","article-title":"Phase I\/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination with the HER-1\/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients with Recurrent Non\u2013Small-Cell Lung Cancer","volume":"23","author":"Herbst","year":"2005","journal-title":"J. Clin. Oncol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3484","DOI":"10.1158\/1078-0432.CCR-08-2904","article-title":"Combined Vascular Endothelial Growth Factor Receptor and Epidermal Growth Factor Receptor (EGFR) Blockade Inhibits Tumor Growth in Xenograft Models of EGFR Inhibitor Resistance","volume":"15","author":"Naumov","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1016\/S1470-2045(14)70381-X","article-title":"Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): An open-label, randomised, multicentre, phase 2 study","volume":"15","author":"Seto","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1016\/S1470-2045(19)30634-5","article-title":"Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"20","author":"Nakagawa","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"9506","DOI":"10.1200\/JCO.2020.38.15_suppl.9506","article-title":"NEJ026: Final Overall Survival Analysis of Bevacizumab plus Erlotinib Treatment for NSCLC Patients Harboring Activating EGFR-Mutations","volume":"15","author":"Maemondo","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1001\/jamaoncol.2020.6758","article-title":"Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients with EGFR T790M\u2013Mutated Non\u2013Small Cell Lung Cancer Previously Treated with Epidermal Growth Factor Receptor\u2013Tyrosine Kinase Inhibitor","volume":"7","author":"Akamatsu","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_93","first-page":"100303","article-title":"RELAY+: Exploratory Study of Ramucirumab Plus Gefitinib in Untreated Patients with EGFR-Mutated Metastatic NSCLC","volume":"3","author":"Nishio","year":"2022","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"9507","DOI":"10.1200\/JCO.2020.38.15_suppl.9507","article-title":"Concurrent Osimertinib plus Gefitinib for First-Line Treatment of EGFR-Mutated Non-Small Cell Lung Cancer (NSCLC)","volume":"38","author":"Rotow","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1758835920930333","DOI":"10.1177\/1758835920930333","article-title":"Application of immune checkpoint inhibitors in EGFR-mutant non-small-cell lung cancer: From bed to bench","volume":"12","author":"Jin","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/S1470-2045(19)30167-6","article-title":"Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): A multicentre, randomised, open-label, phase 3 trial","volume":"20","author":"West","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S2213-2600(19)30084-0","article-title":"Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): Key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial","volume":"7","author":"Reck","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.jtho.2021.09.014","article-title":"IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups with EGFR Mutations or Metastases in the Liver or Brain","volume":"17","author":"Nogami","year":"2021","journal-title":"J. Thorac. Oncol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.jtho.2022.01.012","article-title":"Osimertinib Plus Durvalumab in Patients with EGFR-Mutated, Advanced NSCLC: A Phase 1b, Open-Label, Multicenter Trial","volume":"17","author":"Ahn","year":"2022","journal-title":"J. Thorac. Oncol."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Chan, D.W.-K., Choi, H.C.-W., and Lee, V.H.-F. (2022). Treatment-Related Adverse Events of Combination EGFR Tyrosine Kinase Inhibitor and Immune Checkpoint Inhibitor in EGFR-Mutant Advanced Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Cancers, 14.","DOI":"10.3390\/cancers14092157"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1672","DOI":"10.1016\/S1470-2045(16)30532-0","article-title":"Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: A multicentre, randomised, controlled, phase 2 study","volume":"17","author":"Gomez","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.annonc.2022.02.003","article-title":"ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer","volume":"33","author":"Passaro","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"9014","DOI":"10.1200\/JCO.2022.40.16_suppl.9014","article-title":"Osimertinib plus necitumumab in EGFR-mutant NSCLC: Final results from an ETCTN California Cancer Consortium phase I study","volume":"40","author":"Riess","year":"2022","journal-title":"J. Clin. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/6936\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:37:42Z","timestamp":1760139462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/13\/6936"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":103,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["ijms23136936"],"URL":"https:\/\/doi.org\/10.3390\/ijms23136936","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]}}}