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Ref Type Journal Article
PMID (38456804)
Authors Bashi AC, Coker EA, Bulusu KC, Jaaks P, Crafter C, Lightfoot H, Milo M, McCarten K, Jenkins DF, van der Meer D, Lynch JT, Barthorpe S, Andersen CL, Barry ST, Beck A, Cidado J, Gordon JA, Hall C, Hall J, Mali I, Mironenko T, Mongeon K, Morris J, Richardson L, Smith PD, Tavana O, Tolley C, Thomas F, Willis BS, Yang W, O'Connor MJ, McDermott U, Critchlow SE, Drew L, Fawell SE, Mettetal JT, Garnett MJ
Title Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NRAS Q61L acute myeloid leukemia sensitive AMG 176 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) and Tapotoclax (AMG 176) synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804
NRAS Q61L acute myeloid leukemia sensitive Trametinib + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and Venclexta (venetoclax) synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804
NRAS Q61L acute myeloid leukemia sensitive BCL201 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) and BCL201 (S55746) synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804
NRAS Q61L acute myeloid leukemia sensitive AZD5991 + Selumetinib Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) and AZD5991 synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804
NRAS Q61L acute myeloid leukemia sensitive Selumetinib + Venetoclax Preclinical - Cell culture Actionable In a preclinical study, Koselugo (selumetinib) and Venclexta (venetoclax) synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804
NRAS Q61L acute myeloid leukemia sensitive AZD5991 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and AZD5991 synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804
NRAS Q61L acute myeloid leukemia sensitive AMG 176 + Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) and Tapotoclax (AMG 176) synergistically inhibited viability of an acute myeloid leukemia cell line harboring NRAS Q61L in culture (PMID: 38456804). 38456804