A landscape of response to drug combinations in non-small cell lung cancer

Nishanth Ulhas Nair, Patricia Greninger, Xiaohu Zhang, Adam A. Friedman, Arnaud Amzallag, Eliane Cortez, Avinash Das Sahu, Joo Sang Lee, Anahita Dastur, Regina K. Egan, Ellen Murchie, Michele Ceribelli, Giovanna S. Crowther, Erin Beck, Joseph McClanaghan, Carleen Klump-Thomas, Jessica L. Boisvert, Leah J. Damon, Kelli M. Wilson, Jeffrey Ho, Angela Tam, Crystal McKnight, Sam Michael, Zina Itkin, Mathew J. Garnett, Jeffrey A. Engelman, Daniel A. Haber, Craig J. Thomas, Eytan Ruppin () and Cyril H. Benes ()
Additional contact information
Nishanth Ulhas Nair: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Patricia Greninger: Harvard Medical School
Xiaohu Zhang: Howard Hughes Medical Institute
Adam A. Friedman: Harvard Medical School
Arnaud Amzallag: Harvard Medical School
Eliane Cortez: Harvard Medical School
Avinash Das Sahu: University of New Mexico, Comprehensive Cancer Center
Joo Sang Lee: Sungkyunkwan University School of Medicine
Anahita Dastur: Harvard Medical School
Regina K. Egan: Harvard Medical School
Ellen Murchie: Harvard Medical School
Michele Ceribelli: Howard Hughes Medical Institute
Giovanna S. Crowther: Harvard Medical School
Erin Beck: Howard Hughes Medical Institute
Joseph McClanaghan: Harvard Medical School
Carleen Klump-Thomas: Howard Hughes Medical Institute
Jessica L. Boisvert: Harvard Medical School
Leah J. Damon: Harvard Medical School
Kelli M. Wilson: Howard Hughes Medical Institute
Jeffrey Ho: Harvard Medical School
Angela Tam: Harvard Medical School
Crystal McKnight: Howard Hughes Medical Institute
Sam Michael: Howard Hughes Medical Institute
Zina Itkin: Howard Hughes Medical Institute
Mathew J. Garnett: Wellcome Trust Genome Campus
Jeffrey A. Engelman: Harvard Medical School
Daniel A. Haber: Harvard Medical School
Craig J. Thomas: National Center for Advancing Translational Sciences, National Institute of Health
Eytan Ruppin: Center for Cancer Research, National Cancer Institute, National Institutes of Health
Cyril H. Benes: Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Combination of anti-cancer drugs is broadly seen as way to overcome the often-limited efficacy of single agents. The design and testing of combinations are however very challenging. Here we present a uniquely large dataset screening over 5000 targeted agent combinations across 81 non-small cell lung cancer cell lines. Our analysis reveals a profound heterogeneity of response across the tumor models. Notably, combinations very rarely result in a strong gain in efficacy over the range of response observable with single agents. Importantly, gain of activity over single agents is more often seen when co-targeting functionally proximal genes, offering a strategy for designing more efficient combinations. Because combinatorial effect is strongly context specific, tumor specificity should be achievable. The resource provided, together with an additional validation screen sheds light on major challenges and opportunities in building efficacious combinations against cancer and provides an opportunity for training computational models for synergy prediction.

Date: 2023
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DOI: 10.1038/s41467-023-39528-9

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