EGFR-mutant lung adenocarcinomas treated first-line with the novel EGFR inhibitor, XL647, can subsequently retain moderate sensitivity to erlotinib Journal Article

   

Authors:	Chmielecki, J.; Pietanza, M. C.; Aftab, D.; Shen, R.; Zhao, Z.; Chen, X.; Hutchinson, K.; Viale, A.; Kris, M. G.; Stout, T.; Miller, V.; Rizvi, N.; Pao, W.
Article Title:	EGFR-mutant lung adenocarcinomas treated first-line with the novel EGFR inhibitor, XL647, can subsequently retain moderate sensitivity to erlotinib
Abstract:	Introduction: EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Unfortunately, they develop resistance, often due to acquisition of a second-site mutation (T790M). Current EGFR TKIs select for T790M in preclinical models of acquired resistance. We explored whether all EGFR TKIs similarly select for the T790M mutation using data from early clinical trials and established in vitro models of acquired resistance. Methods: We analyzed the clinical characteristics of eight patients with metastatic EGFR-mutant lung adenocarcinoma who were treated first-line with XL647 and then progressed. XL647 is an ATP-competitive inhibitor of EGFR, HER2, KDR, and EPHB4. Additional molecular preclinical studies were performed to characterize resistance. Results: Four patients displayed confirmed partial responses (PRs), three patients had unconfirmed PRs, and one patient displayed stable disease. Only one of five patients' tumor samples available for analysis after disease progression harbored the T790M mutation. Eight patients subsequently received erlotinib, with (n = 3) or without (n = 5) chemotherapy. Three of five patients treated with single-agent erlotinib derived additional benefit, staying on drug up to 9 months. EGFR-mutant PC-9 cells with acquired resistance to XL647 did not harbor the T790M mutation, displayed a distinct mRNA profile from PC-9 cells with T790M-mediated resistance, and were moderately sensitive to erlotinib in growth inhibition assays. Crystal structure analyses of XL647/EGFR T790M did not reveal a different binding mode from that of erlotinib. Conclusions: The findings of this exploratory study suggest that different EGFR TKIs may select for distinct mechanisms of resistance. These results raise the possibility that different EGFR TKIs could be sequentially used to improve outcomes in patients with EGFR-mutant lung cancer. Further work investigating this hypothesis is warranted. Copyright © 2012 by the International Association for the Study of Lung Cancer.
Keywords:	erlotinib; gefitinib; non-small cell lung cancer; acquired resistance; egfr mutations; afatinib; egfr tyrosine kinase inhibitors; xl647
Journal Title:	Journal of Thoracic Oncology
Volume:	7
Issue:	2
ISSN:	1556-0864
Publisher:	Elsevier Inc.
Date Published:	2012-02-01
Start Page:	434
End Page:	442
Language:	English
DOI:	10.1097/JTO.0b013e31823c5aee
PROVIDER:	scopus
PMCID:	PMC3261336
PUBMED:	22173702
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84858342654&partnerID=40&md5=e077eee781d5365acfa69220b9d34946
Notes:	--- - "Export Date: 2 April 2012" - "Source: Scopus"

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