Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor

Abstract

Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.

Evolution of Patterns of Care and Outcomes in the Real-Life Setting for Patients with Metastatic GIST Treated in Three French Expert Centers over Three Decades

“…The primary objective was to describe clinical and biological profiles as well as treatment modalities of patients with metastatic GIST in a real-life setting, including access to clinical trials and LR procedures in the metastatic setting. Secondary objectives were to assess (1) patients' overall survival (OS) in the metastatic setting; (2) patients' outcome in terms of time to next treatment (TNT) for each line of systemic treatment; (3) the impact of clinical trial inclusion and LR procedures on TNT and OS in the metastatic setting; (4) evolution of patients' treatment modalities and OS among four therapeutics access periods: <2002 (pre-imatinib), 2002-2006 (pre-sunitinib), 2006-2014 (pre-regorafenib), post 2014; and (5) to determine clinical and molecular factors associated with TNT and OS in the metastatic setting, in univariate and multivariate analysis.…”

“…Metastatic GIST are currently treated with oral KIT and PDGFR tyrosine-kinase inhibitors (TKI) such as imatinib, sunitinib and regorafenib [2][3][4]. Over two decades, significant changes in drug discovery and locoregional (LR) procedures have impacted treatment strategies [5][6][7][8]. Recently, two new drugs have been approved in metastatic GIST, namely ripretinib after failure of at least three lines, including imatinib [9], and avapritinib in GIST with the PDGFRA exon 18 D842V mutation [10].…”

Deciphering the tumor immune microenvironment of imatinib-resistance in advanced gastrointestinal stromal tumors at single-cell resolution

“…As verified by many studies, this heterogeneity can result in significant variability of resistance among different tumor lesions, as well as within different regions of a single lesion. It has been established that the primary mechanism of resistance is the polyclonal expansion of cross-resistant subpopulations [ 12 ]. Despite being poorly explored in the management of GIST, preclinical data suggest that immunotherapy may be of interest, particularly in advanced GIST cases [ 13 , 14 ].…”