Ashley Holahan

Necrosis-inducing anticancer therapies robustly activate immune cells and induce immunogenic cell death. This allows for the combination of immunotherapy and necrosis-inducing therapies to treat and target otherwise unresponsive solid tumors. Recently, through a genome-wide CRISPR screen with selection against necrosis inducing agents and follow-up studies, our lab identified a widely expressed monovalent cation membrane channel, TRPM4, as a key necrotic executioner protein that drives necrotic cell swelling. Although the TRPM4 channel has been studied in several systems, its role in breast cancer and most other types of cancer was largely unexplored despite being overexpressed in estrogen receptor positive breast cancer and many other types of cancer. To identify new druggable targets and pathways associated with TRPM4, I have conducted a high-throughput small molecule screen to identify small molecules that selectively reduce cell viability in wild type cells but not in our TRPM4 knockout cells. This has lead us to identify potential cell death activators that appear to funnel through TRPM4-associated pathways. I plan to study these compounds further to assess their therapeutic potential as well as identify key components of their pathways that could be novel druggable targets in cancer cells