Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity - imatinib, sunitinib, and regorafenib - are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.

Bromodomain and extraterminal domain inhibitor enhances the antitumor effect of imatinib in gastrointestinal stromal tumours

“…Imatinib mesylate possibly inhibits the activity of the KIT kinase and is the first‐line drug for unresectable and advanced GIST treatment, attaining at least a limited response in nearly 80% of metastatic patients . Nevertheless, most patients develop resistance to imatinib within 2‐3 years of treatment initiation, making the clinical management of GIST challenging . Therefore, the identification of new treatment targets is required in GIST to expand the treatment choices for patients who are resistant to small‐molecule tyrosine kinase inhibitors, such as imatinib .…”

“…Imatinib, which binds directly to the KIT receptor, was shown to have no appreciable effect on the KIT promoter . BRD4 inhibition resulting from combined therapy minimized KIT dependency and improved the sensitivity to imatinib in resistant GIST cells in vitro and in vivo.…”

“…Indicated protein level was analysed by Western blotting. *P < .05; **P < .01 of GIST challenging 36. Therefore, the identification of new treatment targets is required in GIST to expand the treatment choices for patients who are resistant to small-molecule tyrosine kinase inhibitors, such as imatinib 37.…”

Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth

“…Sunitinib malate, an oral multitargeted inhibitor of KIT, PDGFRA, and vascular endothelial growth factor receptor (VEGFR), is approved for the treatment of imatinib‐resistant GISTs. Regorafenib is used as a third‐line agent (Serrano et al ., ). However, despite an initial response to these targeted agents, tumors invariably become resistant (Kang et al ., ) and new therapeutic approaches are needed to improve the clinical management of GIST patients.…”

Quantitative Mass Spectrometry Imaging Reveals Mutation Status-independent Lack of Imatinib Penetration into Liver Metastases of Gastrointestinal Stromal Tumors

“…Imatinib is the standard first line treatment for GIST, effectively stopping autophosphorylation and tumor proliferation particularly in exon 11 mutated GIST (22)(23)(24). However, tumors are prone to imatinib resistance, which is mainly attributed to secondary somatic mutations in the KIT or the platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases (25,26). In this study, we introduce generalized nonlinear regression as a superior calibration method based on imatinib-containing pixels, report MALDI-qMSI of three full technical replicates, and compare these results [fast time of flight MALDI-TOF-qMSI and ultra-high-resolution Fourier-Transform Ion Cyclotron Resonance (FTICR-qMSI)] with conventional UPLC-ESI-QTOF-MS quantification.…”