Secondary KIT mutations: the GIST of drug resistance and sensitivity.
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ABSTRACT:
SUBMITTER: Napolitano A
PROVIDER: S-EPMC6461933 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Secondary KIT mutations: the GIST of drug resistance and sensitivity.
Napolitano Andrea A Vincenzi Bruno B
British journal of cancer 20190222 6
Pharmacological targeting of KIT in gastrointestinal stromal tumours has dramatically changed the clinical outcome of this disease. Tyrosine kinase inhibitors are the cornerstone of this improvement, but resistance occurs through secondary KIT mutations. Studies aimed at improving our understanding of the molecular basis of sensitivity and resistance will soon allow us to further tailor our therapeutic strategies. ...[more]
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Project description: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.
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