Seminar

Rationale-based therapeutic combinations with PI3K/AKT inhibitors in breast cancer

Maurizio Scaltriti, PhD

The PI3K/AKT/mTOR signaling is important for cell proliferation, survival and metabolism. Hyperactivation of this pathway is one of the most common signaling abnormalities observed in cancer, and thus a substantial effort has been recently made to develop molecules targeting this signaling cascade. However, it is becoming evident that PI3K inhibitors used as single agents do not elicit dramatic or durable responses. There are at least two possible explanations for this. The therapeutic window of these compounds is generally narrow, since normal cells also require the PI3K signaling for survival. As a consequence, severe adverse effects (e.g. hyperglycemia) often manifest before full inhibition of the target in tumor cells. Moreover, inhibition of the PI3K pathway leads to the activation of compensatory pathways that can limit the sensitivity to these agents. Thus, hypothesis-based combinatorial strategies are likely needed to fully exploit their antitumor activity. In this presentation I will propose three different therapeutic strategies (in different breast cancer subtypes) based on both genomic and non-genomic mechanisms of resistance to PI3K/AKT inhibitors.