Abstract ES6-3: Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states

Abstract

Abstract Targeted therapies have demonstrated clinically impactful efficacies. Upfront and adaptive tumor heterogeneity and plasticity present a next challenge to advancing cancer therapeutics further. We are using systems biology and integrative omic approaches towards identifying i) vulnerabilities of aggressive tumor types and ii) combination therapies for preventing resistance. We are incorporating functional datasets defining drug sensitivities (drug screens) and genetic vulnerabilities (shRNA knockdown and CRISPR knockout screens) to identify phenotype-associated cellular susceptibilities. In cancer cells highly dependent upon glucose for survival, we found that glucose withdrawal activates a positive feedback loop involving reactive oxygen species (ROS), ROS-mediated inhibition of tyrosine phosphatases, and tyrosine kinase signaling. This loop amplifies ROS to toxic levels, resulting in cell death. In a process that has parallels to the epithelial to mesenchyme transition (EMT), melanoma cells can undergo dedifferentiation. New standard of care therapies, such as kinase inhibition and immunotherapy, can promote dedifferentiation as a therapy escape route. We found that de-differentiated melanomas have increased sensitivity to ferroptosis - a cell death mechanism tied to metabolism and oxidized lipid membranes. Targeting ferroptosis in combination with standard therapies can block this dedifferentiation resistance escape route. Citation Format: Graeber T. Systems approaches to attacking cancer vulnerabilities defined by metabolic, de-differentiation and genomic instability states [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES6-3.