Abstract 430: Pemigatinib, an FGFR inhibitor, overcomes resistance to KRASG12C inhibitors in mesenchymal-like NSCLC tumors

KRAS is one of the most frequently mutated oncogenes. Clinical studies with recently developed covalent KRASG12C inhibitors have shown promising anticancer activity in patients with KRASG12C tumors (substitution of glycine to cysteine at amino acid 12). Not all KRASG12C patients respond to single-agent treatment or, despite initial responses, develop drug resistance. Here, we investigate therapeutic options to overcome resistance to KRASG12C inhibitor therapy in non-small cell lung cancer (NSCLC). Cancer cell lines and in vivo tumor xenograft models representing high fibroblast growth factor receptor-1 expression (FGFR1hi) and KRASG12C tumors were treated with FGFR or KRASG12C inhibitors. The impact of single-agent versus combination treatment was measured in cell signaling, functional, and in vivo tumor growth assays. Analysis of a genome-wide genetic screen and corresponding mutation and expression data from DepMap identified a subset of NSCLC cells that harbor high FGFR1 expression (FGFR1hi) and KRASG12C mutations. FGFR1hi cancer cells exhibited mesenchymal-like features including high levels of vimentin and low levels of E-cadherin. To assess the functional role of high FGFR1 expression in KRASG12C-mutant cancer cells, pemigatinib, a potent and selective inhibitor of FGFR1-3, was tested alone or in combination with KRASG12C inhibitors. The combination of pemigatinib and KRASG12C inhibitors was synergistic in mesenchymal-like lung cancer cells with high FGFR1 expression, whereas no synergy was observed in cells with low FGFR1 expression. Furthermore, inhibition of FGFR1 activity was essential as a FGFR2-3 specific inhibitor demonstrated only modest activity in combination with KRASG12C inhibitors. Notably, treatment of FGFR1hi KRASG12C LU99 cells with covalent KRASG12C inhibitors resulted in an increase in FRS2 phosphorylation, a marker of FGFR pathway activation, which was suppressed by pemigatinib. To determine whether increased FGFR1 activity may be an acquired resistance mechanism, KRASG12C-mutant Mia-Paca-2 clones resistant to KRASG12C inhibitors were generated. Subsequent protein analysis identified high levels of FGFR1 expression in a subset of resistant clones. In vivo studies with mesenchymal KRASG12C-mutant xenografts confirmed increased antitumor efficacy and inhibition of pERK with the combination of KRASG12C inhibitors and pemigatinib, compared with single-agent treatment. In contrast, in vivo combination activity was not observed in NSCLC