Molecular Comparison of Imatinib-Naïve and Resistant Gastrointestinal Stromal Tumors: Differentially Expressed microRNAs and mRNAs.

Amirnasr Amirnasr,Sciot Sciot,Sleijfer Sleijfer,Van Kuijk Van Kuijk,Rutkowski Rutkowski,Wiemer Wiemer,Debiec-Rychter Debiec-Rychter,Vriends Vriends,Smid Smid,Gits Gits,Schöffski Schöffski

doi:10.3390/cancers11060882

Abstract

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.

Highlights

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal malignancies associated with the gastrointestinal tract that originate from the interstitial cells of Cajal (ICC) or precursors thereof [1].gastrointestinal stromal tumor (GIST) and ICC share morphological and immunophenotypic features, notably the expression of KIT and CD34
To investigate the molecular events underlying the acquisition of imatinib resistance in GIST we first determined the miRNA expression profiles in fresh frozen IM-n (n = 33) and IM-r (n = 20) GIST
To better understand the mechanisms that account for imatinib resistance, here we molecularly characterized at an mRNA and miRNA level a unique set of IM-n and IM-r GIST samples

Summary

Introduction

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal malignancies associated with the gastrointestinal tract that originate from the interstitial cells of Cajal (ICC) or precursors thereof [1].GISTs and ICC share morphological and immunophenotypic features, notably the expression of KIT and CD34. The advent of the tyrosine kinase inhibitor imatinib mesylate, which targets both KIT and PDGFRA, has dramatically improved the outcome of patients with advanced disease [6,7]. Despite this great progress in GIST treatment and the fact that approximately 10% of the patients benefit for more than 10 years from imatinib [8], the majority of patients eventually develop imatinib resistance (acquired resistance) [8] with about 10% of GIST patients experiencing progression already within 6 months of start of therapy (intrinsic resistance) [6,7]. These resistance-causing secondary mutations cluster in two regions: (i) ATP-binding pocket (encoded by exons 13 and 14), and (ii) kinase catalytic regions/activation loop

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Results

Conclusion