EMBO Molecular Medicine (Aug 2023)
ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer
- Christopher W Schultz,
- Yang Zhang,
- Rajaa Elmeskini,
- Astrid Zimmermann,
- Haiqing Fu,
- Yasuhisa Murai,
- Darawalee Wangsa,
- Suresh Kumar,
- Nobuyuki Takahashi,
- Devon Atkinson,
- Liton Kumar Saha,
- Chien‐Fei Lee,
- Brian Elenbaas,
- Parth Desai,
- Robin Sebastian,
- Ajit Kumar Sharma,
- Melissa Abel,
- Brett Schroeder,
- Manan Krishnamurthy,
- Rajesh Kumar,
- Nitin Roper,
- Mirit Aladjem,
- Frank T Zenke,
- Zoe Weaver Ohler,
- Yves Pommier,
- Anish Thomas
Affiliations
- Christopher W Schultz
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Yang Zhang
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Rajaa Elmeskini
- Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc Frederick National Laboratory for Cancer Research Frederick MD USA
- Astrid Zimmermann
- Translational Innovation Platform Oncology Merck KGaA, Biopharma R&D Darmstadt Germany
- Haiqing Fu
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Yasuhisa Murai
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Darawalee Wangsa
- Genetics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Suresh Kumar
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Nobuyuki Takahashi
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Devon Atkinson
- Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc Frederick National Laboratory for Cancer Research Frederick MD USA
- Liton Kumar Saha
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Chien‐Fei Lee
- Translational Innovation Platform Oncology EMD Serono Research and Development Institute Inc., Biopharma R&D Billerica MA USA
- Brian Elenbaas
- Translational Innovation Platform Oncology EMD Serono Research and Development Institute Inc., Biopharma R&D Billerica MA USA
- Parth Desai
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Robin Sebastian
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Ajit Kumar Sharma
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Melissa Abel
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Brett Schroeder
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Manan Krishnamurthy
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Rajesh Kumar
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Nitin Roper
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Mirit Aladjem
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Frank T Zenke
- Translational Innovation Platform Oncology Merck KGaA, Biopharma R&D Darmstadt Germany
- Zoe Weaver Ohler
- Center for Advanced Preclinical Research, Leidos Biomedical Research, Inc Frederick National Laboratory for Cancer Research Frederick MD USA
- Yves Pommier
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- Anish Thomas
- Developmental Therapeutics Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health Bethesda MD USA
- DOI
- https://doi.org/10.15252/emmm.202217313
- Journal volume & issue
-
Vol. 15,
no. 8
pp. n/a – n/a
Abstract
Abstract Small‐cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC‐driven non‐neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high‐throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First‐in‐class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S‐phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC‐driven non‐neuroendocrine tumors which are resistant to first‐line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin–berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.
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