@article{0eb3a2711d4546359f2d508b23cc9e4a,
title = "Translesion DNA synthesis mediates acquired resistance to olaparib plus temozolomide in small cell lung cancer",
abstract = "In small cell lung cancer (SCLC), acquired resistance to DNA-damaging therapy is challenging to study because rebiopsy is rarely performed. We used patient-derived xenograft models, established before therapy and after progression, to dissect acquired resistance to olaparib plus temozolomide (OT), a promising experimental therapy for relapsed SCLC. These pairs of serial models reveal alterations in both cell cycle kinetics and DNA replication and demonstrate both inter- and intratumoral heterogeneity in mechanisms of resistance. In one model pair, up-regulation of translesion DNA synthesis (TLS) enabled tolerance of OT-induced damage during DNA replication. TLS inhibitors restored sensitivity to OT both in vitro and in vivo, and similar synergistic effects were seen in additional SCLC cell lines. This represents the first described mechanism of acquired resistance to DNA damage in a patient with SCLC and highlights the potential of the serial model approach to investigate and overcome resistance to therapy in SCLC.",
author = "Marcello Stanzione and Jun Zhong and Edmond Wong and LaSalle, {Thomas J.} and Wise, {Jillian F.} and Antoine Simoneau and Myers, {David T.} and Sarah Phat and Moshe Sade-Feldman and Lawrence, {Michael S.} and {Kyle Hadden}, M. and Lee Zou and Farago, {Anna F.} and Dyson, {Nicholas J.} and Drapkin, {Benjamin J.}",
note = "Funding Information: We are grateful to the patients and families who participated in these research studies. We thank D. Haber and S. Maheswaran for CTC isolation from patient samples. We thank the current and former members of the Dyson, Zou, Lan, and Elia laboratories for critical discussions and sharing reagents. We thank J. Minna for thoughtful comments on the manuscript. We thank A. Zheng for help and contribution with the cell line survey. This work has been supported by the research fellowship grant from the Deutsche Forschungsgemeinschaft (M.S.), National Cancer Institute grant U01CA220323-A1 (N.J.D.), grant U24CA213274 (N.J.D.; P.I. C. Rudin, MSKCC), Cancer Prevention and Research Institute of Texas (CPRIT) grant RR20007 (B.J.D.), NIH career development award 1K08CA237832 (B.J.D.), a career development awards from the Lung Cancer Research Foundation (B.J.D.), R01CA247232 (M.K.H.), and Norwegian Cancer Society grant 182694 and CCR startup funds (J.F.W.) Publisher Copyright: Copyright {\textcopyright} 2022 The Authors,",
year = "2022",
month = may,
doi = "10.1126/sciadv.abn1229",
language = "English (US)",
volume = "8",
journal = "Science advances",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "19",
}