ATR inhibition augments the efficacy of lurbinectedin in small‐cell lung cancer

• Published in: EMBO molecular medicine 2023-08, Vol.15 (8), p.e17313-n/a
• Main Authors: Schultz, Christopher W, Zhang, Yang, Elmeskini, Rajaa, Zimmermann, Astrid, Fu, Haiqing, Murai, Yasuhisa, Wangsa, Darawalee, Kumar, Suresh, Takahashi, Nobuyuki, Atkinson, Devon, Saha, Liton Kumar, Lee, Chien‐Fei, Elenbaas, Brian, Desai, Parth, Sebastian, Robin, Sharma, Ajit Kumar, Abel, Melissa, Schroeder, Brett, Krishnamurthy, Manan, Kumar, Rajesh, Roper, Nitin, Aladjem, Mirit, Zenke, Frank T, Ohler, Zoe Weaver, Pommier, Yves, Thomas, Anish
• Format: Article
• Language: English
• Subjects: Ataxia; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - metabolism; ATR inhibitor; biomarker; Biomedicine; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Cell cycle; Cell death; Chemotherapy; Cyclin-dependent kinase inhibitor p21; Cytotoxicity; Dihydrofolate reductase; DNA damage; DNA repair; Drugs; EMBO03; EMBO35; Humans; Kinases; Lung cancer; Lung Neoplasms - pathology; Metabolism; Molecular Medicine; Myc protein; Neoplasm Recurrence, Local; neuroendocrine; Neuroendocrine tumors; Organoids; RNA polymerase; SCLC; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; synergy; Tumors
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202217313

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. Synopsis We found that the DNA damaging RNA Pol‐II inhibitor lurbinectedin strongly synergizes with the ATR inhibitor berzosertib in SCLC. This synergy is dependent on berzosertib allowing for continued cell cycle progression in the presence of lurbinectedin induced DNA damage. An unbiased screen revealed maximal synergy between lurbinectedin and the ATR inhibitor berzosertib in SCLC cells. Berzosertib augments lurbinectedin‐induced DNA damage while inhibiting cell cycle checkpoints leading to mitotic catastrophe. Synergy is reduced with high p21 expression as p21 causes G1 arrest. Synergy is increased with high XPG expression as lurbinectedin induced DNA damage is XPG dependent. The recalcitrant non‐neuroendocrine SCLC subtype has high XPG expression and low p21 expression leading to a unique vulnerability to the lurbinectedin‐berzosertib combination, we are currently exploring this combination in the clinic. Graphical Abstract We found that the DNA damaging RNA Pol‐II inhibitor lurbinectedin strongly synergizes with the ATR inhibitor berzosertib in small cell lung cancer. This synergy is dependent on berzosertib allowing for continued cell cycle progression in the presence of lurbinectedin in