Abstract 299: Patient-derived tumor microenvironment models uncover non-autonomous TKI resistance mechanisms in NSCLC

Abstract

Abstract Background: Tyrosine kinase inhibitors (TKI) have yielded great responses in non-small-cell lung cancer (NSCLC) with EGFR mutations and ALK translocations, however these and other targeted therapies are limited by intrinsic and acquired drug resistance. Previous studies looking into relapsed samples largely expanded our understanding of tumor autonomous resistance mechanisms. In this study, we aimed to decipher the non-autonomous mechanisms in vitro by recapitulating the in vivo tumor microenvironment from patient-derived models. Method: Cancer-associated fibroblast cells are isolated directly from EGFR mutant and ALK translocated NSCLC biopsies. Over 20 patient-derived fibroblast (PDF) models have been established for studying the tumor microenvironment's effect on TKI response. Result: We found that many, but not all, PDF cells exert significant resistance to TKIs. Furthermore, there is considerable variability in the degree and secreted factor / mechanism by which they are protecting the tumor cells. These variations are further correlated with patient in vivo response. Conclusion: Together, our results indicate that PDFs are clinically relevant models for deciphering non-autonomous resistance mechanisms, that they are heterogeneous in protecting cancer cells from TKI treatment, and that the resistance mediated by PDFs can be overcome by specific therapeutic combinations. Citation Format: Haichuan Hu, Matthew Niederst, Jeffrey Engelman. Patient-derived tumor microenvironment models uncover non-autonomous TKI resistance mechanisms in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 299.