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Review
. 2022 Jan 31:10:808591.
doi: 10.3389/fcell.2022.808591. eCollection 2022.

Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor

Jiehan Li  1 , Shuning Guo  1 , Zhenqiang Sun  2 , Yang Fu  1   3
Affiliations
Review

Noncoding RNAs in Drug Resistance of Gastrointestinal Stromal Tumor

Jiehan Li et al. Front Cell Dev Biol. .

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor in the gastrointestinal tracts and a model for the targeted therapy of solid tumors because of the oncogenic driver mutations in KIT and PDGDRA genes, which could be effectively inhibited by the very first targeted agent, imatinib mesylate. Most of the GIST patients could benefit a lot from the targeted treatment of this receptor tyrosine kinase inhibitor. However, more than 50% of the patients developed resistance within 2 years after imatinib administration, limiting the long-term effect of imatinib. Noncoding RNAs (ncRNAs), the non-protein coding transcripts of human, were demonstrated to play pivotal roles in the resistance of various chemotherapy drugs. In this review, we summarized the mechanisms of how ncRNAs functioning on the drug resistance in GIST. During the drug resistance of GIST, there were five regulating mechanisms where the functions of ncRNAs concentrated: oxidative phosphorylation, autophagy, apoptosis, drug target changes, and some signaling pathways. Also, these effects of ncRNAs in drug resistance were divided into two aspects. How ncRNAs regulate drug resistance in GIST was further summarized according to ncRNA types, different drugs and categories of resistance. Moreover, clinical applications of these ncRNAs in GIST chemotherapies concentrated on the prognostic biomarkers and novel therapeutic targets.

Keywords: GIST; drug resistance; imatinib mesylate; noncoding RNAs; targeted therapies.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Signaling pathways of GISTs and potential sites where mutations always happen. At cellular level, the four main pathways (PTEN/PI3K/AKT/mTOR, STAT3, RAS/RAF/MEK/ERK and SDH/succinate/HIF-1α) and the significant proteins in the pathways are shown. And the possible mutation sites with their own mutation rates are also exhibited. The red box indicates the possible mutation sites. The blue wave-like arrow shows the activating signals from the receptor tyrosine kinase. And the red arrow shows the stimulatory modification between the proteins, while the blue “T” symbol shows the inhibitory modification.
FIGURE 2
FIGURE 2
The four main mechanisms showing how ncRNAs work in the drug resistance of GIST. In GISTs, ncRNAs regulate the process of drug resistance mainly in the five mechanisms: OXPHOS (with purple background), autophagy (with green background), apoptosis (with orange background), drug target changes (with blue background) and activation of significant signaling pathways (with pink background). For the regulation of OXPHOS, the ncRNA regulate the Complex II on the inner membrane of mitochondrion. NcRNAs also play pivotal roles in the formation of autophagosome, thus modifying the resistance-induced autophagy. The signaling pathway of apoptosis are displayed and the ncRNAs involving in this process are shown, too. The figure in the lower right corner exhibits the transmembrane structure of KIT and the regulation of ncRNAs on KIT. Furthermore, the figures in the lower left corner show the main signaling pathways (PTEN/PI3K/AKT, JAK/STAT3, PTPN18/pFAK and RASSF1A/Hippo pathway), which are the targets of ncRNAs in the resistance. MiRNAs are distinguished from lncRNA by the different shapes. Activating signals from the receptor on the membrane are shown as the blue wave-like arrow. The red arrow represents the stimulatory modification between the proteins, and the blue “T” symbol shows the inhibitory modification.
FIGURE 3
FIGURE 3
Dual regulations of ncRNAs on drug resistance in GISTs. The left half shows the promoted effects of ncRNAs on drug resistance, and the inhibited effects of ncRNAs are exhibited on the right half. NcRNAs transcribed from DNA regulate their targets thus playing roles in the resistance. The yellow arrow indicates that the expression levels of proteins or ncRNAs are up-regulated. And the blue arrow reveals the down-regulated expression levels of proteins or ncRNAs. The red arrow represents the stimulatory moderations, and the blue “T” symbol shows the inhibitory moderations.
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