Abstract 955: Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors

Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs) are sensitive to the EGFR inhibitors erlotinib and gefitinib. In the majority of patients with this type of cancer, EFGR inhibition leads to a dramatic reduction in tumor size coupled with an abatement of symptoms. These responses are temporary, and in most cases the cancers become resistant after an average of one year. Recently, we and others have found that a subset of these cancers transform from NSCLC to SCLC as they acquire resistance to EGFR TKI. Details underlying this novel resistance mechanism are largely undiscovered. To assess the genetic changes associated with NSCLC to SCLC transformation, we carried out next generation sequencing analysis on NSCLC and SCLC resistant tumors. The sequencing results revealed that Rb, along with p53 and PIK3CA were specifically altered in the SCLC transformed tumors. An IHC assay to detect Rb indicated that while 10 out of 10 SCLC transformed cases have loss of Rb, resistant cancers that maintained an NSCLC histology largely retained Rb. To address the mechanism underlying the resistance to EGFR inhibition in these tumors, we demonstrated that upon the transformation to SCLC there is a marked reduction in EGFR expression, suggesting that in transforming to SCLC these cells become a cell type that no longer requires EGFR for their survival. Finally, utilizing cell lines generated from biopsies taken from resistant cancers, we identify the Bcl-2/Bcl-XL inhibitor Abt-263 as a potential therapeutic approach to treat these resistant patients. Together, our results provide details underlying this novel mechanism of resistance to targeted therapy. Citation Format: Matthew J. Niederst, Lecia V. Sequist, Elizabeth L. Lockerman, Angel R. Garcia, Carlotta Costa, Farhiya Mohamoud, Darrell R. Borger, Toshi Shioda, Gad Getz, Anthony J. Iafrate, Mari Mino-Kenudson, Jeffrey A. Engelman. Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2014-955