Despite the success of imatinib in advanced gastrointestinal stromal tumor (GIST) patients, 50% of the patients experience resistance within two years of treatment underscoring the need to get better insight into the mechanisms conferring imatinib resistance. Here the microRNA and mRNA expression profiles in primary (imatinib-naïve) and imatinib-resistant GIST were examined. Fifty-three GIST samples harboring primary KIT mutations (exon 9; n = 11/exon 11; n = 41/exon 17; n = 1) and comprising imatinib-naïve (IM-n) (n = 33) and imatinib-resistant (IM-r) (n = 20) tumors, were analyzed. The microRNA expression profiles were determined and from a subset (IM-n, n = 14; IM-r, n = 15) the mRNA expression profile was established. Ingenuity pathway analyses were used to unravel biochemical pathways and gene networks in IM-r GIST. Thirty-five differentially expressed miRNAs between IM-n and IM-r GIST samples were identified. Additionally, miRNAs distinguished IM-r samples with and without secondary KIT mutations. Furthermore 352 aberrantly expressed genes were found in IM-r samples. Pathway and network analyses revealed an association of differentially expressed genes with cell cycle progression and cellular proliferation, thereby implicating genes and pathways involved in imatinib resistance in GIST. Differentially expressed miRNAs and mRNAs between IM-n and IM-r GIST were identified. Bioinformatic analyses provided insight into the genes and biochemical pathways involved in imatinib-resistance and highlighted key genes that may be putative treatment targets.

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Keywords GIST, miRNA, mRNA expression, imatinib, drug resistance, gene networks, IPA pathway analysis
Persistent URL dx.doi.org/10.3390/cancers11060882, hdl.handle.net/1765/118840
Journal Cancers
Citation
Amirnasr, A., Gits, C.M.M, van Kuijk, P.F, Smid, M, Vriends, A.L.M., Rutkowski, P, … Wiemer, E.A.C. (2019). Molecular Comparison of Imatinib-Naive and Resistant Gastrointestinal Stromal Tumors: Differentially Expressed microRNAs and mRNAs. Cancers, 11(6). doi:10.3390/cancers11060882