Abstract 1012: Patient-derived tumor microenvironment models uncover nonautonomous TKI resistance mechanisms in NSCLC

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 study from our group was looking into tumor autonomous resistance mechanisms by developing patient-derived cancer models (PDCs). In this study, we aimed to decipher the non-autonomous resistance mechanisms via tumor microenvironment by developing patient-derived fibroblast (PDF) cell lines. Method: Cancer-associated fibroblast cells are isolated directly from EGFR mutant and ALK translocated NSCLC biopsies. Over 30 PDFs models have been established, which represent different clinical features and response profiles. Result: By co-culturing the PDCs with PDFs, we found that there is considerable variability in both models for their magnitude and mechanism by which the TKI treatment is desensitized. Both HGF dependent and HGF independent resistance mechanisms can be overcome by specific therapeutic combinations. 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, Hillary Mulvey, Sundus Noeen, Kodack David, Aaron Hata, Matthew Niederst, Cyril Benes, Jeffrey Engelman. Patient-derived tumor microenvironment models uncover nonautonomous TKI resistance mechanisms in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1012. doi:10.1158/1538-7445.AM2017-1012