Expression of fibroblast growth factor receptor 1 correlates inversely with the efficacy of single‐agent fibroblast growth factor receptor‐specific inhibitors in pancreatic cancer

Abstract

Background and PurposeElevated fibroblast growth factor receptor (FGFR) activity correlates with pancreatic adenocarcinoma (PDAC) progression and poor prognosis. However, its potential as a therapeutic target remains largely unexplored.Experimental ApproachThe mechanisms of action and therapeutic effects of selective pan‐FGFR inhibitors (pan‐FGFRi) were explored using in vitro and in vivo PDAC models ranging from gemcitabine‐sensitive to highly gemcitabine‐resistant (GemR). Gain‐/loss‐of‐function investigations were employed to define the role of individual FGFRs in cell proliferation, migration, and treatment response and resistance.ResultsThe pan‐FGFRi NVP‐BGJ398 (infigratinib) significantly inhibited cell proliferation, migration, and invasion, and downregulated key cell survival‐ and invasiveness markers in multiple PDAC cell lines. Gemcitabine is a standard‐of‐care for PDAC, and GemR development compromises its efficacy. Acquired GemR was modeled experimentally by developing highly GemR cells using escalating Gem exposure in vitro and in vivo. FGFRi treatment inhibited GemR cell proliferation, migration, GemR marker expression, and tumor progression. FGFR2 or FGFR3 loss‐of‐function by shRNA knockdown failed to decrease cell growth, whereas FGFR1 knockdown was lethal. FGFR1 overexpression promoted cell migration more than proliferation, and reduced FGFRi‐mediated inhibition of proliferation and migration. Single‐agent FGFRi suppressed the viability and growth of multiple patient‐derived xenografts inversely with respect to FGFR1 expression, underscoring the influence of FGFR1‐dependent tumor responses to FGFRi. Importantly, secondary data analysis showed that PDAC tumors expressed FGFR1 at lower levels than did normal pancreas tissue.Conclusions and ImplicationsSingle‐agent FGFRi’s mediate selective, molecularly‐targeted suppression of PDAC proliferation, and their effects are greatest in PDAC tumors expressing low‐ to‐moderate FGFR1.

Genetic Signature of Human Pancreatic Cancer and Personalized Targeting

“…There are other FGFR2 inhibitors such as pemigatinib [117] and infigratinib [118,119] which have been tested in cholangiocarcinoma but not in pancreatic cancer. At the cell level, infigratinib showed important inhibition of proliferation and invasion of PDAC cell lines [120].…”

Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors

“…In PDX #14312, which has higher baseline expression of mesenchymal features such as N-cadherin, single-agent FGFRi reduced both N-cadherin expression and the area occupied by tumor cells (Supplementary Fig. S11A-F; p<0.05), suggesting greater activity of single-agent FGFRi in high-EMT models (41). Notably, FGFR1 expression levels also correlate inversely with PDAC tumor sensitivity to single-agent FGFRi (41).…”

“…S11A-F; p<0.05), suggesting greater activity of single-agent FGFRi in high-EMT models (41). Notably, FGFR1 expression levels also correlate inversely with PDAC tumor sensitivity to single-agent FGFRi (41). After 7d of SHHi treatment, 3d of FGFRi treatment altered #18269 tumor architecture markedly, largely restoring an epithelioid tumor cell phenotype, reverting the densely-folded glandular structures to a histological organization resembling controls, and reducing the area occupied by tumor cells, including tumor cell colonies embedded in stroma (Fig.…”