KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST

Abstract

Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance.

A bibliometric analysis of interstitial cells of Cajal research

“…A meta-analysis shows that neoadjuvant chemotherapy may improve 5 years overall survival, while local excision reduces hospitalization time ( 67 ). Recent studies have shown significant differences between GIST and wild-type (WT) KIT mutations, offering potential therapeutic perspectives and targets for overcoming imatinib resistance ( 69 ). Despite some progress in current therapeutic approaches, the outcome for certain GIST patients remains suboptimal.…”

Transfer Learning in Cancer Genetics, Mutation Detection, Gene Expression Analysis, and Syndrome Recognition

“…Two of the most mutated genes in GIST are the KIT and PDGFRA gene mutations [ 68 ]. Identifying these mutations is vital as there is specific therapy for them [ 69 , 70 ]. A CNN model was proposed by Liang et al (2021) [ 42 ] to identify the KIT and PDGFRA gene mutations based on the histologic images.…”