PT  - JOURNAL ARTICLE
AU  - Avinash Das
AU  - Joo Sang Lee
AU  - Gao Zhang
AU  - Zhiyong Wang
AU  - Ramiro Iglesias-Bartolome
AU  - Tian Tian
AU  - Zhi Wei
AU  - Benchun Miao
AU  - Nishanth Ulhas Nair
AU  - Olga Ponomarova
AU  - Adam A. Friedman
AU  - Arnaud Amzallag
AU  - Tabea Moll
AU  - Gyulnara Kasumova
AU  - Patricia Greninger
AU  - Regina K. Egan
AU  - Leah J. Damon
AU  - Dennie T. Frederick
AU  - Allon Wagner
AU  - Kuoyuan Cheng
AU  - Seung Gu Park
AU  - Welles Robinson
AU  - Kevin Gardner
AU  - Genevieve Boland
AU  - Sridhar Hannenhalli
AU  - Meenhard Herlyn
AU  - Cyril Benes
AU  - J. Silvio Gutkind
AU  - Keith Flaherty
AU  - Eytan Ruppin
TI  - Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy
AID  - 10.1101/284240
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 284240
4099  - http://biorxiv.org/content/early/2018/04/08/284240.short
4100  - http://biorxiv.org/content/early/2018/04/08/284240.full
AB  - 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 an adaptive alteration of another gene (the rescuer). Here we perform a genome-wide prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients’ response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.