Gastrointestinal stromal tumors: Arbutus unedo L. as a source of novel chemotherapeutics & mechanisms behind metastasis

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms frequently caused by a gain of function mutation in KIT or PDGFRα, two tyrosine kinase receptors (TKR). For this reason, they are successfully treated with imatinib, a tyrosine kinase inhibitor (TKI). However, the therapy is typically long-term ineffective due to imatinib resistance, which represents the main issue in the clinic of GISTs. Although numerous efforts have been made in the last two decades to develop novel therapies for imatinib-resistant GISTs, the approvals of multi-target TKIs have only improved the clinical outcomes modestly. Emblematic is the recent failure of ripretinib in the phase III INTRIGUE trial, decisively marking the end of the paradigm only based on the central role of KIT secondary mutations in imatinib resistance, and the consequent seeking of multi-target TKIs as the solution. Consistent with this clinical result, preclinical studies have revealed numerous mechanisms of resistance that are not targetable with multi-target TKIs, indicating that imatinib resistance is more multifaceted than initially hypothesized and explaining the modest efficacy of these latter. In this scenario, the absence of drugs capable of long-term counteracting the rise of imatinib-resistant subclones unavoidably leads to progressive disease and metastasis. In particular, the onset of metastases remarkably impacts the median overall survival and determines the most GIST-related deaths. Therefore, new therapy proposals are needed. Here, we present two project lines investigating novel strategies to counteract imatinib-resistant GISTs.