A narrative review of imatinib-resistant gastrointestinal stromal tumors

Abstract

Objective: Review the studies that investigate the mechanisms underlying imatinib-resistant gastrointestinal stromal tumors (GIST). Background: GIST are the most common mesenchymal tumors of the gastrointestinal (GI) tract and the most common sarcoma in humans. GIST are thought to be arise from interstitial cells of Cajal (ICC), pacemaker and neuromodulator cells in the GI tract, as well as "fibroblast"-like cells, which are another type of interstitial cells of the gut wall and also known as telocyte or platelet-derived growth factoralpha (PDGFRA)-positive cells. The majority of GIST harbor gain-of-function mutations in either KIT or PDGFRA, and these gain-of-function mutations are mutually exclusive and most often heterozygous.GIST are responsive to the KIT/PDGFRA tyrosine kinase inhibitor (TKI), imatinib, the standard firstline drug for advanced and metastatic GIST. However, imatinib alone does not eradicate GIST despite an initial clinical benefit, and more than 90% of GIST harbor imatinib-resistance. Although second and thirdgeneration TKIs have been developed and are currently in clinical use, they are not curative for refractory and metastatic GIST due to the emergence of clones with drug-resistant mutations. Eradication of drugresistant GIST will cure patients with refractory GIST. Several mechanisms may contribute to refractory GIST. These mechanisms are secondary mutations in KIT and/or PDGFRA, alternative activation of tyrosine kinases, stem cells for GIST and cellular quiescence, a reversible nonproliferating state in which cells retain the ability to reenter cell proliferation. Methods: We review our current optimal treatment approach for managing patients with advanced and refractory GIST. Conclusions: This review explores the novel and potential therapeutic approaches to combat drugresistant GIST.

Cellular Senescence, Inflammation, and Cancer in the Gastrointestinal Tract

“…Notably, the protein that causes DREAM complex formation, DYRK1A, has an inverse relationship with both cyclin D1 and p21 [ 86 ]. The presence of quiescent cells often leads to imatinib-resistant GIST [ 87 ]. Furthermore, a recent study showed that imatinib-resistant GIST is highly affected by cyclin D1 targeting via proteasome inhibitors, which often leads to cell cycle arrest as well as the expression of p53 and p21 [ 88 ].…”

Aging of enteric neuromuscular systems in gastrointestinal tract

“…28 Unlike ICC, Kit low CD34 + CD44 + ICC stem cells (ICC-SC) do proliferate and serve to continually replenish ICC. 29,30 Recent studies found ICC-SC decline precedes ICC decline with age, suggesting ICC-SC decline may play a major role in age-related ICC loss and gastric motor dysfunctions. 31 Upregulated transformation-related protein 53 (Trp53; a tumor suppressor protein also known as an aging-related transcription factor) induced persistent ICC-SC cell cycle arrest leading to ICC loss without an increase in senescence or apoptosis (Figure 2).…”

“…Previous work has identified a subset of cells immunopositive for CD34 and CD44 with low Kit expression as ICC stem/precursor cells in murine stomach 28 . Unlike ICC, Kit low CD34 + CD44 + ICC stem cells (ICC‐SC) do proliferate and serve to continually replenish ICC 29,30 . Recent studies found ICC‐SC decline precedes ICC decline with age, suggesting ICC‐SC decline may play a major role in age‐related ICC loss and gastric motor dysfunctions 31 .…”

Tumor-associated telocytes

“…Gastrointestinal stromal tumors (GISTs) were first described as mesenchymal neoplasms in 1983, and they perform a similar immunological and morphological features of the ICC, which is homologous to the characteristics of TCs. [ 17 ] The source of TCs in GISTs was confirmed to originate from primitive hepatic biliary ducts-tree, but have functions within the extrahepatic biliary tree system. TCs were demonstrated to contribute to the gall bladder motility and the pathogenesis of bladder related diseases.…”