Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

Overview

Journal Cancer Discov

Specialty Oncology

Date 2024 Mar 8

PMID 38456804

Authors

Azadeh C Bashi

Elizabeth A Coker

Krishna C Bulusu

Patricia Jaaks

Claire Crafter

Howard Lightfoot

Marta Milo

Katrina McCarten

David F Jenkins

Dieudonne van der Meer

James T Lynch

Syd Barthorpe

Courtney L Andersen

Simon T Barry

Alexandra Beck

Justin Cidado

Jacob A Gordon

Caitlin Hall

James Hall

Iman Mali

Tatiana Mironenko

Kevin Mongeon

James Morris

Laura Richardson

Paul D Smith

Omid Tavana

Charlotte Tolley

Frances Thomas

Brandon S Willis

Wanjuan Yang

Mark J OConnor

Ultan McDermott

Susan E Critchlow

Lisa Drew

Stephen E Fawell

Jerome T Mettetal

Mathew J Garnett

Affiliations

Soon will be listed here.

Abstract

Significance: We present the largest cancer drug combination screen published to date with 7 × 7 concentration response matrices for 109 combinations in more than 750 cell lines, complemented by multi-omics predictors of response and identification of "emergent" combination biomarkers. We prioritize hits to optimize clinical translatability, and experimentally validate novel combination hypotheses. This article is featured in Selected Articles from This Issue, p. 695.

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References

McMahon C, Ferng T, Canaani J, Wang E, Morrissette J, Eastburn D . Clonal Selection with RAS Pathway Activation Mediates Secondary Clinical Resistance to Selective FLT3 Inhibition in Acute Myeloid Leukemia. Cancer Discov. 2019; 9(8):1050-1063. DOI: 10.1158/2159-8290.CD-18-1453. View

ONeil J, Benita Y, Feldman I, Chenard M, Roberts B, Liu Y . An Unbiased Oncology Compound Screen to Identify Novel Combination Strategies. Mol Cancer Ther. 2016; 15(6):1155-62. DOI: 10.1158/1535-7163.MCT-15-0843. View

Boshuizen J, Peeper D . Rational Cancer Treatment Combinations: An Urgent Clinical Need. Mol Cell. 2020; 78(6):1002-1018. DOI: 10.1016/j.molcel.2020.05.031. View

Boehm J, Garnett M, Adams D, Francies H, Golub T, Hahn W . Cancer research needs a better map. Nature. 2021; 589(7843):514-516. DOI: 10.1038/d41586-021-00182-0. View

Corcoran R, Ebi H, Turke A, Coffee E, Nishino M, Cogdill A . EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012; 2(3):227-35. PMC: 3308191. DOI: 10.1158/2159-8290.CD-11-0341. View

Close D, Wang A, Kochanek S, Shun T, Eiseman J, Johnston P . Implementation of the NCI-60 Human Tumor Cell Line Panel to Screen 2260 Cancer Drug Combinations to Generate >3 Million Data Points Used to Populate a Large Matrix of Anti-Neoplastic Agent Combinations (ALMANAC) Database. SLAS Discov. 2018; 24(3):242-263. DOI: 10.1177/2472555218812429. View

Plana D, Palmer A, Sorger P . Independent Drug Action in Combination Therapy: Implications for Precision Oncology. Cancer Discov. 2022; 12(3):606-624. PMC: 8904281. DOI: 10.1158/2159-8290.CD-21-0212. View

Zagidullin B, Aldahdooh J, Zheng S, Wang W, Wang Y, Saad J . DrugComb: an integrative cancer drug combination data portal. Nucleic Acids Res. 2019; 47(W1):W43-W51. PMC: 6602441. DOI: 10.1093/nar/gkz337. View

BERENBAUM M . The expected effect of a combination of agents: the general solution. J Theor Biol. 1985; 114(3):413-31. DOI: 10.1016/s0022-5193(85)80176-4. View

10.

Dunn S, Eberlein C, Yu J, Gris-Oliver A, Ong S, Yelland U . AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors. Oncogene. 2022; 41(46):5046-5060. PMC: 9652152. DOI: 10.1038/s41388-022-02482-9. View

11.

Lauchle J, Kim D, Le D, Akagi K, Crone M, Krisman K . Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature. 2009; 461(7262):411-4. PMC: 4119783. DOI: 10.1038/nature08279. View

12.

Carter J, Hege K, Yang J, Kalpage H, Su Y, Edwards H . Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther. 2020; 5(1):288. PMC: 7746731. DOI: 10.1038/s41392-020-00361-x. View

13.

Lehar J, Zimmermann G, Krueger A, Molnar R, Ledell J, Heilbut A . Chemical combination effects predict connectivity in biological systems. Mol Syst Biol. 2007; 3:80. PMC: 1828746. DOI: 10.1038/msb4100116. View

14.

Tao Z, Hasvold L, Wang L, Wang X, Petros A, Park C . Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity. ACS Med Chem Lett. 2014; 5(10):1088-93. PMC: 4190639. DOI: 10.1021/ml5001867. View

15.

Bailey M, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A . Comprehensive Characterization of Cancer Driver Genes and Mutations. Cell. 2018; 173(2):371-385.e18. PMC: 6029450. DOI: 10.1016/j.cell.2018.02.060. View

16.

Jain N, Curran E, Iyengar N, Diaz-Flores E, Kunnavakkam R, Popplewell L . Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2013; 20(2):490-8. PMC: 4310865. DOI: 10.1158/1078-0432.CCR-13-1311. View

17.

Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S . The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses. Curr Protoc Bioinformatics. 2016; 54:1.30.1-1.30.33. DOI: 10.1002/cpbi.5. View

18.

Yu C, Mannan A, Yvone G, Ross K, Zhang Y, Marton M . High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines. Nat Biotechnol. 2016; 34(4):419-23. PMC: 5508574. DOI: 10.1038/nbt.3460. View

19.

Garcia-Alonso L, Iorio F, Matchan A, Fonseca N, Jaaks P, Peat G . Transcription Factor Activities Enhance Markers of Drug Sensitivity in Cancer. Cancer Res. 2017; 78(3):769-780. PMC: 6522379. DOI: 10.1158/0008-5472.CAN-17-1679. View

20.

Angius G, Tomao S, Stati V, Vici P, Bianco V, Tomao F . Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development. Cancer Chemother Pharmacol. 2019; 85(1):9-20. DOI: 10.1007/s00280-019-03950-y. View