Abstract B70: Participation of fibroblast growth factor receptors (FGFRs) in acquired resistance to EGFR-specific TKIs in NSCLC.

Abstract

Abstract Despite initial and often dramatic responses of specific NSCLC tumors to EGFR TKIs such as gefitinib and erlotinib, nearly all develop resistance and eventually relapse. We have investigated both rapid and chronic mechanisms of resistance to EGFR-specific TKIs in lung cancer cell lines. Following 3 to 4 day treatments with gefitinib, FGFR2 and FGFR3 mRNA and protein are selectively and rapidly (24 to 48 hrs) increased in NSCLC cell lines in which EGFR is the dominant oncogenic driver via mutation or amplification. This induction is mediated, in part, by transcriptional mechanisms and indicates that EGFR signaling functions to repress expression of FGFR2 and FGFR3. Moreover, EGFR TKI-induced FGFR2 and FGFR3 are capable of mediating FGF-stimulated ERK activation and transformed growth in the continued presence of EGFR TKIs. These studies highlight FGFR2 and FGFR3 induction as a rapid molecular response that may modulate initial sensitivity of EGFR-driven lung tumors to EGFR-specific TKIs. We have also employed NSCLC cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs, gefitinib (reversible) and BIBW2992 (irreversible), through chronic (2–3 months) adaptation in tissue culture. To date, three (HCC4006, H1650, HCC2279) of the eight chronically-adapted NSCLC cell lines exhibit a marked induction of FGF2 and FGFR1 upon acquisition of gefitinib resistance (Table 1). Additionally, two of eight undergo marked loss of epithelial differentiation as measured by decreased E-cadherin. The induction of FGFR1 was not mediated by gene amplification as assessed by FISH analysis. Importantly, these chronically-adapted cell lines were highly sensitive to both FGFR-specific TKIs and an FGF ligand trap, FP-1039, as measured by ERK signaling and growth assays. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs may provide a novel autocrine receptor tyrosine kinase-driven growth pathway in a subset of lung tumors that were initially sensitive to EGFR-specific TKIs. We are presently exploring the in vivo relevance of this mechanism using primary tumor specimens obtained pretreatment and following tumor progression on EGFR-specific TKIs. Combined, these studies indicate that FGFR-specific TKIs may be valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to reduce acquired resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B70.