Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy.

Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy.

Publication date: Mar 11, 2019

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 in silico 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.

Sahu, A.D., S Lee, J., Wang, Z., Zhang, G., Iglesias-Bartolome, R., Tian, T., Wei, Z., Miao, B., Nair, N.U., Ponomarova, O., Friedman, A.A., Amzallag, A., Moll, T., Kasumova, G., Greninger, P., Egan, R.K., Damon, L.J., Frederick, D.T., Jerby-Arnon, L., Wagner, A., Cheng, K., Park, S.G., Robinson, W., Gardner, K., Boland, G., Hannenhalli, S., Herlyn, M., Benes, C., Flaherty, K., Luo, J., Gutkind, J.S., and Ruppin, E. Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy. 21945. 2019 Mol Syst Biol (15):3.

Concepts Keywords
Combinatorial Transcriptomics
Genome Targeted immunotherapy
Immunotherapy Drug resistance
Melanoma Transcriptomics technologies
Targeted Therapies Virotherapy
Transcriptomics Immunotherapy
Tumor Immunology
Branches of biology
Clinical medicine
Medicine
Immunotherapy
Melanoma
Tumor

Semantics

Type Source Name
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
disease DOID cancer
disease MESH cancer

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