Molecular Mechanisms of Resistance in Epidermal Growth Factor Receptor-mutant Lung Adenocarcinomas

Overview

Journal Eur Respir Rev

Specialty Pulmonary Medicine

Date 2014 Sep 2

PMID 25176972

Citations 81

Authors

Alexis B Cortot

Pasi A Janne

Affiliations

Soon will be listed here.

Abstract

The discovery of epidermal growth factor receptor (EGFR) mutations in nonsmall cell lung cancer (NSCLC) has allowed the identification of a subset of patients whose tumours are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). Despite the efficacy and superiority of EGFR TKIs over chemotherapy as first-line therapy, all patients will ultimately develop progressive disease, with a median of 9-13 months progression-free survival. A better understanding of the molecular mechanisms underlying resistance to EGFR TKIs can help design new drugs and therapeutic strategies to overcome resistance. This has been illustrated by the new generation TKIs that are effective on the T790M mutation, which is the most frequent mechanism of acquired resistance to EGFR TKIs. In this article, we will address the main molecular mechanisms of primary and acquired resistance to EGFR TKIs in EGFR-mutant NSCLC.

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References

Kuiper J, Heideman D, Thunnissen E, Paul M, van Wijk A, Postmus P . Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. Lung Cancer. 2014; 85(1):19-24. DOI: 10.1016/j.lungcan.2014.03.016. View

Godin-Heymann N, Ulkus L, Brannigan B, McDermott U, Lamb J, Maheswaran S . The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther. 2008; 7(4):874-9. DOI: 10.1158/1535-7163.MCT-07-2387. View

Gong Y, Somwar R, Politi K, Balak M, Chmielecki J, Jiang X . Induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors in mutant EGFR-dependent lung adenocarcinomas. PLoS Med. 2007; 4(10):e294. PMC: 2001209. DOI: 10.1371/journal.pmed.0040294. View

Pluquet E, Cadranel J, Legendre A, Faller M, Souquet P, Zalcman G . Osteoblastic reaction in non-small cell lung carcinoma and its association to epidermal growth factor receptor tyrosine kinase inhibitors response and prolonged survival. J Thorac Oncol. 2010; 5(4):491-6. DOI: 10.1097/JTO.0b013e3181cf0440. View

Mok T, Wu Y, Thongprasert S, Yang C, Chu D, Saijo N . Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009; 361(10):947-57. DOI: 10.1056/NEJMoa0810699. View

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

Weinstein I . Cancer. Addiction to oncogenes--the Achilles heal of cancer. Science. 2002; 297(5578):63-4. DOI: 10.1126/science.1073096. View

Riely G, Pao W, Pham D, Li A, Rizvi N, Venkatraman E . Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2006; 12(3 Pt 1):839-44. DOI: 10.1158/1078-0432.CCR-05-1846. View

Ogino A, Kitao H, Hirano S, Uchida A, Ishiai M, Kozuki T . Emergence of epidermal growth factor receptor T790M mutation during chronic exposure to gefitinib in a non small cell lung cancer cell line. Cancer Res. 2007; 67(16):7807-14. DOI: 10.1158/0008-5472.CAN-07-0681. View

10.

Chmielecki J, Foo J, Oxnard G, Hutchinson K, Ohashi K, Somwar R . Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med. 2011; 3(90):90ra59. PMC: 3500629. DOI: 10.1126/scitranslmed.3002356. View

11.

Sharma S, Lee D, Li B, Quinlan M, Takahashi F, Maheswaran S . A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010; 141(1):69-80. PMC: 2851638. DOI: 10.1016/j.cell.2010.02.027. View

12.

Filosto S, Baston D, Chung S, Becker C, Goldkorn T . Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells. Mol Cancer Ther. 2013; 12(8):1579-90. PMC: 4370317. DOI: 10.1158/1535-7163.MCT-12-1029. View

13.

Engelman J, Settleman J . Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev. 2008; 18(1):73-9. DOI: 10.1016/j.gde.2008.01.004. View

14.

Ohashi K, Sequist L, Arcila M, Moran T, Chmielecki J, Lin Y . Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci U S A. 2012; 109(31):E2127-33. PMC: 3411967. DOI: 10.1073/pnas.1203530109. View

15.

Arcila M, Oxnard G, Nafa K, Riely G, Solomon S, Zakowski M . Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res. 2011; 17(5):1169-80. PMC: 3070951. DOI: 10.1158/1078-0432.CCR-10-2277. View

16.

La Monica S, Caffarra C, Saccani F, Galvani E, Galetti M, Fumarola C . Gefitinib inhibits invasive phenotype and epithelial-mesenchymal transition in drug-resistant NSCLC cells with MET amplification. PLoS One. 2013; 8(10):e78656. PMC: 3805532. DOI: 10.1371/journal.pone.0078656. View

17.

Beau-Faller M, Prim N, Ruppert A, Nanni-Metellus I, Lacave R, Lacroix L . Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network. Ann Oncol. 2013; 25(1):126-31. PMC: 3868323. DOI: 10.1093/annonc/mdt418. View

18.

Rosell R, Molina M, Costa C, Simonetti S, Gimenez-Capitan A, Bertran-Alamillo J . Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin Cancer Res. 2011; 17(5):1160-8. DOI: 10.1158/1078-0432.CCR-10-2158. View

19.

Yasuda H, Park E, Yun C, Sng N, Lucena-Araujo A, Yeo W . Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med. 2013; 5(216):216ra177. PMC: 3954775. DOI: 10.1126/scitranslmed.3007205. View

20.

Arcila M, Nafa K, Chaft J, Rekhtman N, Lau C, Reva B . EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther. 2013; 12(2):220-9. PMC: 3714231. DOI: 10.1158/1535-7163.MCT-12-0620. View