<p>Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an <em>omic</em> approach to identify novel druggable targets</p>

Abstract

Background: Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance. Methods: For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells. Results: We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism. Conclusion: Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets.

MicroRNA‐based recombinant AAV vector assembly improves efficiency of suicide gene transfer in a murine model of lymphoma

“…To further validate the involvement of MAPK pathway during AAV packaging, we performed an immunoblotting assay with a site‐specific antibody [p44/42 MAPK (Erk1/2)]. This antibody specifically recognizes phosphorylated (Thr202/Tyr204) Erk1/2, indicating the activation of the MAPK signaling pathway, as previously reported . Our data presented in Figure , demonstrate that phosphorylated forms of MAPK are downregulated in the quadruple packaging method.…”

“…This antibody specifically recognizes phosphorylated (Thr202/ Tyr204) Erk1/2, indicating the activation of the MAPK signaling pathway, as previously reported. 58 Our data presented in Figure 5, demonstrate that phosphorylated forms of MAPK are downregulated in the quadruple packaging method.…”

Casticin inhibits nasopharyngeal carcinoma growth by targeting phosphoinositide 3-kinase

“…As a result, manipulating PI3K-mediated alterations has become an attractive target for cancer therapy, and great efforts are underway to develop effective PI3K inhibitors. In this regard, BYL719, a pan-PI3K inhibitor, is being tested in clinical trials for esophageal squamous cell carcinoma (ESCC), metastatic head and neck squamous cell carcinoma, gastrointestinal stromal tumours, breast cancer, and ovarian cancer [10, 11]. However, it is difficult to conduct in-depth research because of the emergence of drug resistance.…”

Alpelisib Inhibits PIK3CA-Mutant Breast Cancer Growth Through AKT-Dependent Bim Induction and Mcl-1 Degradation

“…Promising results were observed in breast tumor patients harboring PIK3CA mutations (15,16). There were some bene ts of these agents, but typical relapse was observed even in patients who initially had a positive response after a month of treatment (17). With the ER-positive nature of the majority of PIK3CA-mutant tumors, it may be stipulated that these cells can survive through both pathways governing proliferation and survival (18).…”