Cancer therapies aim to kill tumor cells, but many instead establish a state of cell cycle arrest known as therapy-induced senescence (TIS). Paradoxically, TIS may provide an escape route for tumor cells, such that they can become resistant to drug-induced apoptosis, continue to exert pro-tumor and pro-metastatic activities as well as local immunosuppression, and resurface and proliferate at a later stage, often more aggressively. TIS is now recognized as a major contributor to failed cancer treatments, yet unlike classical cellular senescence which is well-defined, we still know very little about the biology of cells that have entered TIS. There is a great need for model systems that can deliver insights into TIS.
In this ASPIRE award, Shom Goel will focus on two critical mediators of cellular senescence, the tumor suppressor genes TP53 and RB1, which are commonly mutated in cancers. Goel will develop novel genetically engineered mouse models of breast cancer, exhibiting loss-of-function of TP53 or RB1. His team aims to understand how these tumor suppressors influence the nature and phenotype of TIS. Using high-throughput compound screens, breast cancer cell lines and tumor-derived organoids from the mouse models in this proposal, Goel and his team plan to identify potential senolytics (small molecules that induce senescent cancer cell death). Their long-term goal is to develop synergistic therapies tailored to a patient’s tumor mutational profile by first inducing TIS, and then administering senolytics that can selectively kill TIS cells.
Goel S, Bergholz JS, Zhao JJ. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer. 2022.