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 that we have conducted. We show that the SR interactions successfully predict cancer patients’ response and emerging resistance and that the targeting of predicted rescuer genes re-sensitizes resistant cancer cells. These results provide novel rationale-based combinatorial approaches for proactively overcoming therapy resistance. Finally, going beyond targeted therapy, we show that the SR analysis can successfully predict molecular alterations conferring resistance to immunotherapy in melanoma patients.
[Work led by Avinash Das and Joo Sang Lee in my lab, in collaboration with the labs of Silvio Gutkind (UCSD), Cyril Benes (MGH), Keith Flaherty & Genevieve Boland (MGH) and Meenhard Herlyn (Wistar).]