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Large-scale Pan-cancer Cell Line Screening Identifies Actionable and Effective Drug Combinations.
Bashi, Azadeh C; Coker, Elizabeth A; Bulusu, Krishna C; Jaaks, Patricia; Crafter, Claire; Lightfoot, Howard; Milo, Marta; McCarten, Katrina; Jenkins, David F; van der Meer, Dieudonne; Lynch, James T; Barthorpe, Syd; Andersen, Courtney L; Barry, Simon T; Beck, Alexandra; Cidado, Justin; Gordon, Jacob A; Hall, Caitlin; Hall, James; Mali, Iman; Mironenko, Tatiana; Mongeon, Kevin; Morris, James; Richardson, Laura; Smith, Paul D; Tavana, Omid; Tolley, Charlotte; Thomas, Frances; Willis, Brandon S; Yang, Wanjuan; O'Connor, Mark J; McDermott, Ultan; Critchlow, Susan E; Drew, Lisa; Fawell, Stephen E; Mettetal, Jerome T; Garnett, Mathew J.
Afiliação
  • Bashi AC; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Coker EA; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Bulusu KC; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Jaaks P; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Crafter C; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Lightfoot H; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Milo M; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • McCarten K; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Jenkins DF; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • van der Meer D; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Lynch JT; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Barthorpe S; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Andersen CL; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Barry ST; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Beck A; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Cidado J; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Gordon JA; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Hall C; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Hall J; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Mali I; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Mironenko T; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Mongeon K; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Morris J; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Richardson L; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Smith PD; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Tavana O; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Tolley C; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Thomas F; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • Willis BS; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Yang W; Wellcome Sanger Institute, Cambridge, United Kingdom.
  • O'Connor MJ; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • McDermott U; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Critchlow SE; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Drew L; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Fawell SE; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Mettetal JT; Oncology R&D, AstraZeneca, Waltham, Massachusetts.
  • Garnett MJ; Wellcome Sanger Institute, Cambridge, United Kingdom.
Cancer Discov ; 14(5): 846-865, 2024 May 01.
Article em En | MEDLINE | ID: mdl-38456804
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.

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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Neoplasias Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article