Resistance Mechanisms and Novel Therapeutic Opportunities in Gastrointestinal Stromal Tumors (GISTs)

In the last two decades, the research has progressively highlighted that both genetic and epigenetic alterations are involved and contribute to cancer pathogenesis, progression and treatment outcome. The knowledge of epigenomics is continuously growing and we are gradually figuring out its importance in regulating gene expression and biological processes. However, clinical translation has been very scarce. GISTs are rare sarcoma tumors, which represent the most common mesenchymal tumor of the GI tract. During the ESMO Sarcoma and GIST Symposium 2018, epigenetics has been included among the new avenues in soft tissue sarcomas and GISTs. In GISTs, however, the advances in epigenetics have been quite scarce. The PhD project aimed to deepen the knowledge on epigenetics in GISTs. Specifically, the research had two goals: the first one was to investigate and characterize the differences in miRNAs expression levels, comparing KIT/PDGFRA mutant and KIT/PDGFRA wild-type GISTs. Secondly, we aimed to elucidate mechanisms of pharmacological resistance to a PI3KCA inhibitor (BYL719) in GISTs who previously failed imatinib and sunitinib treatment. With regard to the first goal, we identified an epigenetic mechanism involved in regulating the IGF1R expression. In particular, in agreement with the literature, our data revealed that miR-139-5p has a role of tumor suppressor and its inhibition promoted cell migration and invasion. Second, through an omic approach in in-vitro models, we characterized a mechanism of resistance involving epigenetic alterations. Specifically, after confirmed the absence of resistance mutations, we integrated miRNA and methylation profiles with gene expression. This led us to speculate that BYL719 resistance could be mediated by alternative mechanisms, which confer advantages to the cells. Herein we showed that epigenetics in GISTs could be more important than it has been thought so far. In particular, we showed that epigenetic mechanisms are involved in the pathogenesis, as well as in resistance.