TY - JOUR
T1 - ATR inhibition augments the efficacy of lurbinectedin in small-cell lung cancer
AU - Schultz, Christopher W
AU - Zhang, Yang
AU - Elmeskini, Rajaa
AU - Zimmermann, Astrid
AU - Fu, Haiqing
AU - Murai, Yasuhisa
AU - Wangsa, Darawalee
AU - Kumar, Suresh
AU - Takahashi, Nobuyuki
AU - Atkinson, Devon
AU - Saha, Liton Kumar
AU - Lee, Chien-Fei
AU - Elenbaas, Brian
AU - Desai, Parth
AU - Sebastian, Robin
AU - Sharma, Ajit Kumar
AU - Abel, Melissa
AU - Schroeder, Brett
AU - Krishnamurthy, Manan
AU - Kumar, Rajesh
AU - Roper, Nitin
AU - Aladjem, Mirit
AU - Zenke, Frank T
AU - Ohler, Zoe Weaver
AU - Pommier, Yves
AU - Thomas, Anish
N1 - Publisher Copyright:
© 2023 The Authors. Published under the terms of the CC BY 4.0 license. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
PY - 2023/8/7
Y1 - 2023/8/7
N2 - 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.
AB - 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.
KW - Humans
KW - Neoplasm Recurrence, Local
KW - Small Cell Lung Carcinoma/drug therapy
KW - Lung Neoplasms/pathology
KW - Carcinoma, Non-Small-Cell Lung/drug therapy
KW - Ataxia Telangiectasia Mutated Proteins/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85165584812&partnerID=8YFLogxK
U2 - 10.15252/emmm.202217313
DO - 10.15252/emmm.202217313
M3 - Article
C2 - 37491889
SN - 1757-4676
VL - 15
SP - e17313
JO - EMBO molecular medicine
JF - EMBO molecular medicine
IS - 8
M1 - e17313
ER -
