American Association for Cancer Research
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Figure 4 from Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations

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posted on 2024-05-01, 07:43 authored by 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. O'Connor, Ultan McDermott, Susan E. Critchlow, Lisa Drew, Stephen E. Fawell, Jerome T. Mettetal, Mathew J. Garnett

Combination activity of selumetinib plus venetoclax or AZD5991 in AML. A and B, Combo Emax versus HSA scores in 19 AML cell lines exposed to selumetinib combined with (a) venetoclax or (b) AZD5991. C and D, NOMO1 growth inhibition and HSA excess to the combination of selumetinib with (c) venetoclax or (d) AZD5991. E and F, Western blot analysis for apoptosis markers in NOMO1 cells following time course treatment with selumetinib (300 nmol/L) combined with (e) venetoclax (300 nmol/L) or (f) AZD5991 (100 nmol/L). G, Tumor growth in NOMO1 xenografts treated with selumetinib, AZD5991, or venetoclax alone or in combination for 28 days (n = 5 each arm). Control and monotherapy experimental arms were halted once the maximum permitted tumor volume (2,000 cm3) was reached. Data are plotted as mean tumor volume ± SEM.

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Wellcome Trust (WT)

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ARTICLE ABSTRACT

Oncology drug combinations can improve therapeutic responses and increase treatment options for patients. The number of possible combinations is vast and responses can be context-specific. Systematic screens can identify clinically relevant, actionable combinations in defined patient subtypes. We present data for 109 anticancer drug combinations from AstraZeneca's oncology small molecule portfolio screened in 755 pan-cancer cell lines. Combinations were screened in a 7 × 7 concentration matrix, with more than 4 million measurements of sensitivity, producing an exceptionally data-rich resource. We implement a new approach using combination Emax (viability effect) and highest single agent (HSA) to assess combination benefit. We designed a clinical translatability workflow to identify combinations with clearly defined patient populations, rationale for tolerability based on tumor type and combination-specific “emergent” biomarkers, and exposures relevant to clinical doses. We describe three actionable combinations in defined cancer types, confirmed in vitro and in vivo, with a focus on hematologic cancers and apoptotic targets. 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