The most common type of gastrointestinal mesenchymal tumour is gastrointestinal stromal tumours (GISTs). Carcinogenesis of GISTs is caused by gain-of-function mutations in KIT or plateletderived growth factor receptor (PDGFRA), which result in constitutive activation of the tyrosine kinase and its downstream signalling cascades. Imatinib, a KIT/PDGFRA inhibitor, is the standard of care for patients with metastatic GISTs, and oncogenic KIT or PDGFRA mutations are promising therapeutic targets for GISTs. In the majority of GIST patients, however, clinical resistance to imatinib and other tyrosine kinase inhibitors develops. (1) acquisition of a secondary point mutation in KIT or PDGFRA; (2) genomic amplification of KIT; (3) activation of an alternative receptor tyrosine kinase; (4) reduction of KIT oncoprotein production; and (5) wild-type GIST have all been identified as mechanisms of resistance. Sunitinib is a second-line treatment for people who have failed imatinib, while regorafenib is approved for people who have failed both imatinib and sunitinib. Novel inhibitors and immunotherapies targeting KIT and its downstream effectors such as phosphatidylinositol 3-kinase are now being evaluated in phase trials. Heat shock protein 90, histone deacetylase inhibitor, and protein kinase B and mammalian target of rapamycin Potential targets include ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A. As prospective new GIST therapeutic targets, these candidates should be investigated in the clinic.
Author (s) Details
Jia-Qing Zhu
College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018, Hangzhou, Zhejiang Province, China.
Wen-Bin Ou
College of Life Sciences and Medicine, Zhejiang Sci-Tech University, 310018, Hangzhou, Zhejiang Province, China and Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, Hangzhou, 310018, Zhejiang Province, China.
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