The ability of cancer cells to resist apoptotic death induced by radiation, chemotherapy, targeted therapies and immunotherapy has been a primary impediment to achieving long-lasting clinical responses. Cancer resistance is often studied through the lens of genetics, and thus on a drug-by-drug basis. I will discuss an alternative approach - studying resistance through the lens of cellular plasticity. As part of the NCI’s Cancer Target Discovery & Development Network, we use the Cancer Therapeutics Response Portal (CTRP), which enables small molecule sensitivity-cancer cell feature relationships to be explored on a broad basis. One insight gained from this resource suggests that a similar form of plasticity appears recurrently in multiple cancer contexts, and in response to multiple modalities (chemotherapy; targeted therapy; immunotherapy) thus opening the possibility of a pan-cancer explanation of resistance. Here, cell plasticity provides access to an apoptosis-deficient state and thus resistance, and then subsequent cancer mutations, rather than being the basis of resistance, are needed to optimize the fitness of the resistant state for growth. We found that this myofibroblastic-like cell state has profound changes in lipid biology that result in a novel vulnerability to ferroptotic cell death and a dependency on the activity of GPX4, a potentially druggable lipid hydroperoxidas. We hope this research will provide a blueprint for the cure of cancers in the future.

Citation Format: Stuart L. Schreiber. Chemical biology-based approach to understanding and overcoming resistance of cancers to therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-01.