Abstract 4455: Studies of early adaptive resistance in mutant-EGFR and EML4-ALK addicted non-small cell lung cancer in escape against small molecule inhibitors.

Abstract

Abstract Lung cancer is the second most common malignancy in the United States with the highest cancer-mortality rate. Molecular targeted therapy in oncogene addicted non-small cell lung cancer (NSCLC) has gain landmark proof-of-principle success in clinical utility in recent years. Prime examples are EGFR targeted therapy against mutated EGFR tumors using tyrosine kinase inhibitors (TKIs) such as erlotinib/gefitinib, and also ALK targeted therapy against EML4-ALK tumors using ALK inhibitor crizotinib. Superior response rates and progression free survival outcomes were observed with the use of targeted therapeutics even in first line setting. Nonetheless, targeted therapeutics against mutant-EGFR and EML4-ALK tumors invariably develop an acquired tumor resistance to the TKIs. Mutational resistant mechanism has been well-established. Alternative signal pathway activation such as MET/HGF in both EGFR and ALK TKI resistance, or HER family signaling activation in EML4-ALK resistance have also been reported. We have recently begun studies focusing on the non-mutational mechanisms of tumor resistance under early time window of TKI treatment. Using HCC827 and PC9 cells as mutant EGFR addiction model, as well as H3122 and H2228 NSCLC cells as EML4-ALK addicted model, we have uncovered a novel early adaptive TKI resistance that can be evident as early as 7-14 days under initial TKI treatment. The early adaptive tumor cells displayed remarkable tumor resistance against the TKIs with 100-fold higher IC50. In mutant-EGFR against erlotinib, there was an upregulated mitochondrial antiapoptotic/prosurvival BCL-2/BCL-xL signaling dependence that is MET-independent. The early resistant cells were adaptive, highly reversible and adopted a quiescent state during TKI-induced resistance. On the other hand, our studies of early TKI resistance in EML4-ALK fusion cells revealed that while the adaptive resistance to TAE684 was also reversible, it appears to be not dependent on BCL-2/BCL-xL upregulation. We found that in both targeted TKI early resistance, the tumor survivor cells exhibited epithelial-mesenchymal transition (EMT) markers changes with decreased E-cadherin expression and increased vimentin expression. Our studies also provided in vitro and in vivo evidence that these early adaptive TKI resistant tumor cells can be targetable for prevention or eradication of tumor resistance emergence, such as utilizing BCL-2/BCL-xL pathway inhibitors, such as ABT-737, in combination with EGFR TKI in mutant-EGFR addicted NSCLC. Further preclinical model studies will focus on investigating the molecular and genomic changes and gene network regulation in the early adaptive resistant tumor cells, to enable a new paradigm of novel therapeutic targets discovery to overcome early tumor resistance emergence and improve long term outcome of targeted therapy in lung cancer. Citation Format: Lihong Yin, Ivy Shi, Wei Zhang, Rakesh Bagai, Yan Feng, Patrick C. Ma. Studies of early adaptive resistance in mutant-EGFR and EML4-ALK addicted non-small cell lung cancer in escape against small molecule inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4455. doi:10.1158/1538-7445.AM2013-4455