FGFR blockade inhibits targeted therapy-tolerant persister cells in basal FGFR1 and FGF2 high expressing cancers with driver oncogenes

Abstract

Abstract Cancer cell resistance arises when tyrosine kinase inhibitor (TKI)-targeted therapies induce a drug-tolerant persister (DTP) state with growth via genetic aberrations, making DTP cells potential therapeutic targets. We screened an anti-cancer compound library and identified fibroblast growth factor receptor 1 (FGFR1) promoting alectinib-induced ALK fusion-positive DTP cell's survival. FGFR1 signaling promoted DTP cell survival generated from basal FGFR1- and FGF2-high expressing cells, following alectinib treatment, which is blocked by FGFR inhibition. The hazard ratio for progression-free survival of ALK-TKIs tended to increase in ALK fusion-positive non-small cell lung cancer patients with FGFR1- and FGF2-high expression. Combination of FGFR and targeted TKIs enhanced cell growth inhibition in FGFR1- and FGF2-high expressing cells with ALK fusion, HER2 amplification, and EGFR or BRAF mutations. Initial dual blockade of FGFR and various driver oncogenes based on FGFR1 and FGF2 expression levels before starting treatment would be a potent treatment strategy to prevent intrinsic resistance to targeted TKIs through DTP cells.