A landscape of response to drug combinations in non-small cell lung cancer
-
Published:2023-06-28
Issue:1
Volume:14
Page:
-
ISSN:2041-1723
-
Container-title:Nature Communications
-
language:en
-
Short-container-title:Nat Commun
Author:
Nair Nishanth UlhasORCID, Greninger PatriciaORCID, Zhang Xiaohu, Friedman Adam A., Amzallag Arnaud, Cortez Eliane, Sahu Avinash Das, Lee Joo SangORCID, Dastur Anahita, Egan Regina K., Murchie Ellen, Ceribelli Michele, Crowther Giovanna S., Beck Erin, McClanaghan Joseph, Klump-Thomas CarleenORCID, Boisvert Jessica L., Damon Leah J., Wilson Kelli M.ORCID, Ho Jeffrey, Tam Angela, McKnight Crystal, Michael Sam, Itkin Zina, Garnett Mathew J.ORCID, Engelman Jeffrey A., Haber Daniel A.ORCID, Thomas Craig J.ORCID, Ruppin EytanORCID, Benes Cyril H.ORCID
Abstract
AbstractCombination 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference91 articles.
1. Leon-Buitimea, A., Garza-Cardenas, C. R., Garza-Cervantes, J. A., Lerma-Escalera, J. A. & Morones-Ramirez, J. R. The demand for new antibiotics: antimicrobial peptides, nanoparticles, and combinatorial therapies as future strategies in antibacterial agent design. Front. Microbiol. 11, 1669 (2020). 2. Johnson, M. D. & Perfect, J. R. Use of antifungal combination therapy: agents, order, and timing. Curr. Fungal Infect. Rep. 4, 87–95 (2010). 3. Daar, E. S. Novel approaches to HIV therapy. F1000Res. 6, 759 (2017). 4. Doroshow, J. H. & Simon, R. M. On the design of combination cancer therapy. Cell 171, 1476–1478 (2017). 5. Frei, E. 3rd et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 26, 642–656 (1965).
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|