Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	14	5	2024 May 01	846-865	Cancer Discov

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 + 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
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	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	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	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	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	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