Abstract 2371: Heterogeneity of resistance mechanisms in lung adenocarcinoma patients with acquired resistance to EGFR inhibitors

Abstract

Abstract Drug resistance is a major obstacle in overcoming cancer. Understanding the origin, extent and heterogeneity of resistance mechanisms within a patient is crucial to guide treatment and developing drugs/combinations to circumvent resistance. To this end, we studied autopsy samples collected from four EGFR-mutant lung adenocarcinoma patients who developed resistance to EGFR inhibitors. We used whole-exome sequencing to characterize genomic profiles of multiple metastasis tumors within each patient. To address the challenge of non-uniform variant detection power at sequenced genetic loci across multiple samples, we developed a computational framework that tackles variant detection from pooled tumor followed by a genotyping module. After the identification of somatic alterations, we determined the extent of heterogeneity of resistance mechanisms between multiple tumor samples. Our results revealed that multiple metastasis samples in a single patient can potentially use one common resistance mechanism. For example, one patient harbored a resistant EGFR T790M mutation in all 11 metastasis samples with a correlated allele frequency to the original L858R mutation. However, in some other cases, we found heterogeneous resistance mechanisms coexisting in multiple metastasis samples with various allele frequencies. For instance, one patient harbored both the resistance EGFR T790M mutation and an activating PIK3CA E542K mutation that appear with a range of allelic frequencies in multiple metastatic samples. Furthermore, branched evolutionary patterns of tumors were constructed using a phylogenetic approach, which inform resistance in the context of tumor evolution. Our findings are consistent with the model that cells harboring a variety of resistance mechanisms coexist in each metastasis tumor, and those subclones with higher selective advantage outgrow the others. Citation Format: Xinmeng Jasmine Mu, Eli Van Allen, Nikhil Wagle, Curtis Chong, Mohit Butaney, Deborah Farlow, Gad Getz, Pasi A. Jänne, Levi A. Garraway. Heterogeneity of resistance mechanisms in lung adenocarcinoma patients 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 2371. doi:10.1158/1538-7445.AM2014-2371