Ricerc@Sapienza

Overexpression of the anti-apoptotic Bcl-2 family proteins is commonly observed in hematological malignancies, including Acute Myeloid Leukemia (AML). Hence, strategies to inhibit Bcl-2 family proteins have been extensively investigated over the years, showing high in vitro and in vivo efficacy.
ABT-199 (Venetoclax) is a BH3-mimetic, selective for Bcl-2, which demonstrated a pronounced antineoplastic activity, receiving FDA approval for the treatment of CLL and AML. However, primary or secondary resistance ensued after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Among other factors, resistance to Venetoclax appear related to stromal interaction and to the metabolic reprogramming of leukemic blasts. Evidences show that Venetoclax exposure induce a reduction in the oxidative metabolism, and that the simultaneous targeting of metabolism can restore sensitivity to the Bcl-2 inhibitor. A further resistance mechanism has been identified in the cross-talk between Bcl-2 and other signaling pathway, as Venetoclax seems to upregulate Mcl-1 via signaling mediated by ERK.
Given the strict interplay between metabolism and signaling, aim of this study will be to elucidate to what extend both processes concur in the acquisition of BH3-mimetic resistance in AML. We will generate Venetoclax-resistant derived cell lines. The characterization of the metabolic phenotype and the phospho-proteomic profile associated to resistant phenotype will be the start point for the generation of novel BH3 mimetic-based treatment combination strategies able to overcome resistance. Finally, the resulting optimal combination will be tested on AML primary cells.
Results of this study can help to identify additional molecular targets to be pharmacologically addressed in the design of new, more effective therapeutic strategies involving Venetoclax on AML patients.