Claudin-1 contributes to gastrointestinal stromal tumors (GIST) resistance to imatinib mesylate (IM) via regulation of FGFR2-mediated signaling.
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. Overall design: Resistance to the targeted therapy in GIST is a significant limitation of treatment efficacy.  This study aimed to examine the role of claudin 1 (CLDN1) in GIST resistance to imatinib mesylate (IM). To examine the molecular mechanisms involved in CLDN1-mediated resistance of GIST to IM, we initially performed transcriptome profiling of IM-resistant GIST-T1 (GIST-T1R) cells transfected with siCLDN1 or treated with PDS-0330.