TY - JOUR
T1 - Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress
AU - Thomas, Anish
AU - Takahashi, Nobuyuki
AU - Rajapakse, Vinodh N.
AU - Zhang, Xiaohu
AU - Sun, Yilun
AU - Ceribelli, Michele
AU - Wilson, Kelli M.
AU - Zhang, Yang
AU - Beck, Erin
AU - Sciuto, Linda
AU - Nichols, Samantha
AU - Elenbaas, Brian
AU - Puc, Janusz
AU - Dahmen, Heike
AU - Zimmermann, Astrid
AU - Varonin, Jillian
AU - Schultz, Christopher W.
AU - Kim, Sehyun
AU - Shimellis, Hirity
AU - Desai, Parth
AU - Klumpp-Thomas, Carleen
AU - Chen, Lu
AU - Travers, Jameson
AU - McKnight, Crystal
AU - Michael, Sam
AU - Itkin, Zina
AU - Lee, Sunmin
AU - Yuno, Akira
AU - Lee, Min Jung
AU - Redon, Christophe E.
AU - Kindrick, Jessica D.
AU - Peer, Cody J.
AU - Wei, Jun S.
AU - Aladjem, Mirit I.
AU - Figg, William Douglas
AU - Steinberg, Seth M.
AU - Trepel, Jane B.
AU - Zenke, Frank T.
AU - Pommier, Yves
AU - Khan, Javed
AU - Thomas, Craig J.
N1 - Publisher Copyright:
© 2021
PY - 2021/4/12
Y1 - 2021/4/12
N2 - Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.
AB - Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.
KW - DNA damage response
KW - DNA topoisomerases
KW - SCLC
KW - ataxia telangiectasia mutated and rad3 related
KW - cell-cycle checkpoints
KW - replication stress
KW - small cell neuroendocrine cancers
KW - translational research
UR - http://www.scopus.com/inward/record.url?scp=85103707502&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2021.02.014
DO - 10.1016/j.ccell.2021.02.014
M3 - Article
C2 - 33848478
AN - SCOPUS:85103707502
SN - 1535-6108
VL - 39
SP - 566-579.e7
JO - Cancer Cell
JF - Cancer Cell
IS - 4
ER -