Targeting aneuploidy in breast cancer progression; finanziato dall’Unione europea – Next Generation EU

This proposal builds on the convergence of two independent research lines from the proponent labs (Profs. E. Hirsch and S. Pece) sharing the overarching goal of defining key molecular determinants involved in the acquisition of aneuploidy in cancer, with a special focus on breast cancer, which might represent actionable therapeutic targets for treatment of breast cancer patients. The rationale is based on accumulating evidence suggesting that drugs enhancing aneuploidy in cancer cells already carrying an abnormal chromosome count, i.e. compounds targeting cell cycle as well as spindle assembly checkpoint (SAC) proteins, can force cancer cells beyond a critical threshold, leading to mitotic catastrophe and cell death (1, 2). Based on these assumptions, we intend to develop sufficient mechanistic knowledge over the course of the grant that will allow us to exploit newly identified molecular determinants of aneuploidy and chromosomal instability. These tumor-initiating as well as tumor-progression determinants are likely involved in modulating anti- vs. pro-tumorigenic pathways and potentially constitute amenable therapeutic targets to curb tumorigenesis and/or revert therapy resistance. In particular, the proposal points to characterize the role of two tumor suppressor proteins, the Phosphatidylinositol 4-Kinase Alpha (PI4KA) (Hirsch’s lab, Point 1 below) and the cell fate determinant, Numb (Pece’s lab, Point 2 below) as key elements to maintain cellular homeostasis and genomic integrity. This is based on a set of published and unpublished (see preliminary data) data indicating that dysfunction of these 2 proteins can lead to aneuploidy and genetic instability