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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01136

Pan-cancer analysis of potential synthetic lethal drug targets specific to alterations in DNA damage response

  • 1National Institutes of Health (NIH), United States
  • 2National Cancer Institute, National Institutes of Health (NIH), United States
  • 3Radiation Oncology Branch (NCI), United States
  • 4National Cancer Institute (NCI), United States

Alterations in DNA damage response (DDR) is one of the several hallmarks of cancer. Genomic instability resulting from a disrupted DDR mechanism is known to contribute to cancer progression, and are subjected to classical radiation therapies, cytotoxic therapies or more recent targeted therapies with limited success. Synthetic lethality (SL), which is a condition where simultaneous loss-of-function of the genes from complementary pathways result in loss of viability of cancer cells, have been exploited to treat malignancies resulting from defects in certain DDR pathways. Albeit being a promising therapeutic strategy, number of SL based drugs currently in clinical trial is limited. In this work we performed a comprehensive pan-cancer analysis of alterations in 10 DDR pathways with different components of DNA repair. Using unsupervised clustering of single sample enrichment of these pathways in 7272 tumor samples from 17 tumor types from TCGA, we identified 3 prominent clusters, each associated with specific DDR mechanisms. Somatic mutations in key DDR genes were found to be dominant in each of these 3 clusters with distinct DDR component. Using a machine-learning based algorithm we predicted SL partners specific to somatic mutations in key genes representing each of the 3 DDR clusters and identified potential druggable targets. We explored the potential FDA-approved drugs for targeting the predicted SL genes and tested the sensitivity of these drugs in cell lines with mutation in the primary DDR genes using drug screening data. We have shown clinical relevance, for selected targetable SL interactions using Kaplan-Meier analysis in terms of improved disease-free survival. Thus, our computational framework provides a basis for clinically relevant and actionable SL based drug targets specific to alterations in DDR pathways.

Keywords: synthetic lethality, Single sample gene enrichment, mutual exclusivity, somatic mutations, Cancer, DNA damage response

Received: 22 Aug 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Das, Camphausen and Shankavaram. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Uma Shankavaram, National Institutes of Health (NIH), Bethesda, 9000, Maryland, United States, uma@mail.nih.gov