Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations
Acquired resistance of gastrointestinal stromal tumors (GISTs) to imatinib mesylate (IM) is one of the most critical challenges in GIST therapy. Here we show that a long-term culture of GIST T-1 cells with IM induces clonal heterogeneity resulting in the appearance of cancer cells exhibiting activation of the FGFR-signaling pathway which was associated with KIT loss. The first one was due to the overexpression of FGFR1/2 and increased production of FGF-2 ligand. These events maintained GIST resistance to IM and rendered these GIST cells highly sensitive to all types of pan-FGFR-inhibitors used in the current study. Knockout of FGFR2 in this GIST subclone significantly attenuated pro-apoptotic and anti-proliferative activities of infigratinib (BGJ 398) both in vitro and in vivo, thereby suggesting the activation of FGFR-signaling pathway via FGFR2-mediated axis as the predominant molecular mechanism in these GIST cells. Collectively, the extended inhibition of KIT-signaling in GISTs induces clonal heterogeneity of cancer cells and might change the tumor's sensitivity to FGFR-inhibitors due to selection of cancer cells with an FGFR-overactivated pathway. For siCLDN1-transfected and PDS-0330-treated GIST T-1 cell line transcriptomes see GSE296175. Overall design: The transcriptomes of naive (imatinib mesylate sensitive) GIST-T1 cells and their IM-resistant counterparts GIST-R1 and GIST-R2 cells. GIST T-1 was established from a metastatic pleural tumor from a stomach and contains heterozygous 57-base pair deletion (V570-Y578) in KIT exon 11. IM-resistant GIST-R1 subline was established in our laboratory after a continuous induction from 0.4 nM to 1000 nM IM in a stepwise increasing concentration manner. GIST-R2 subclone was derived from GIST-R1 cells continuously treated with IM for up to 12 months.