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Penn Bioinformatics Forum – Eytan Ruppin, MD, PhD
October 11 @ 3:00 pm - 4:00 pm
Genome wide identification of genes mediating cancer resistance to targeted and immune therapy
Dr. Eytan Ruppin
Professor, Center for Bioinformatics and Computational Biology & Dept. of Computer Science, the University of Maryland
University of Maryland
Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by the adaptive alteration of another gene (the rescuer). Here we perform a genome-wide identification of SR-mediated resistance determinants by analyzing the tumor transcriptomics and survival data of 10,000 cancer patients. Predicted SR interactions are validated versus publicly available resistance data and new experimental screens. We show that SRs can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes re-sensitizes resistant cancer cells, providing novel rationale-based combinatorial approaches for proactively overcoming resistance to targeted therapy. Finally, we show that the SR analysis of melanoma patients successfully identifies known molecular alterations conferring resistance to immunotherapy and predicts novel ones.
Reception to follow.