@article{8880a046a8b94b8980e13e5b4b5d9d1b,
title = "MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically",
abstract = "Evasion of programmed cell death represents a critical form of oncogene addiction in cancer cells. Understanding the molecular mechanisms underpinning cancer cell survival despite the oncogenic stress could provide a molecular basis for potential therapeutic interventions. Here we explore the role of pro-survival genes in cancer cell integrity during clonal evolution in non-small cell lung cancer (NSCLC). We identify gains of MCL-1 at high frequency in multiple independent NSCLC cohorts, occurring both clonally and subclonally. Clonal loss of functional TP53 is significantly associated with subclonal gains of MCL-1. In mice, tumour progression is delayed upon pharmacologic or genetic inhibition of MCL-1. These findings reveal that MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically.",
keywords = "BCL-2 FAMILY, CANCER, SURVIVAL, KRAS, PROTEINS, MOUSE, LYMPHOCYTES, EXPRESSION, INHIBITORS, DOCETAXEL",
author = "Enkhtsetseg Munkhbaatar and Michelle Dietzen and Deepti Agrawal and Martina Anton and Moritz Jesinghaus and Melanie Boxberg and Nicole Pfarr and Pidassa Bidola and Sebastian Uhrig and Ulrike H{\"o}ckendorf and Anna-Lena Meinhardt and Adam Wahida and Irina Heid and Rickmer Braren and Ritu Mishra and Arne Warth and Thomas Muley and Poh, {Patrina S P} and Xin Wang and Stefan Fr{\"o}hling and Katja Steiger and Julia Slotta-Huspenina and {van Griensven}, Martijn and Franz Pfeiffer and Sebastian Lange and Roland Rad and Magda Spella and Stathopoulos, {Georgios T} and J{\"u}rgen Ruland and Florian Bassermann and Wilko Weichert and Andreas Strasser and Caterina Branca and Mathias Heikenwalder and Charles Swanton and Nicholas McGranahan and Jost, {Philipp J}",
note = "Funding Information: The authors thank the members of the TRACERx consortium for participating in this study. The results published here are in part based upon data generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. The authors would like to thank S Schwamberger and I Konrad for mouse handling, and Life Science Editors for editing assistance. We thank David Huang for gift of antibodies. The authors would like to thank Gewebebank des Klinikums rechts der Isar und der Technischen Universit{\"a}t M{\"u}nchen, A Terron Kwiatkowski, A Jacob, R. {\"O}llinger, and G Sannino for the excellent technical support. We thank Martin Schuler for critical discussion of the data. Grant Support Grant support by the Mildred Scheel Professorship program from the Deutsche Krebshilfe (program #70113247), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation – FOR 2036, SFB 1335 (Project-ID 360372040), SFB 1371), German Consortium for Translational Cancer Research (DKTK) to P.J.J.; the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation - SFB 1335 (Project-ID 360372040), SFB 1371) to K.S. A.S. is supported by National Health and Medical Research Council (NHMRC) project grant 1143105, NHMRC program grant 1016701, NHMRC fellowship 1020363, Cancer Council of Victoria (CCV) project grant 1052309 and a CCV Venture Grant. N.M is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals. F.B. receives grants from the European Research Commission (project BCM-UPS, grant #682473) and the Deutsche Forschungsgemeinschaft (SFB 1335 and SFB1243). Funding Information: S.F. has had a consulting or advisory role, received honoraria, research funding, and/or travel/accommodation expenses from the following for-profit companies: Bayer, Roche, Amgen, Eli Lilly, PharmaMar, AstraZeneca, and Pfizer. W.W. has attended Advisory Boards and served as speaker for Roche, MSD, BMS, AstraZeneca, Pfizer, Merck, Lilly, Boehringer, Novartis, Takeda, Amgen and Astellas. W.W. receives research funding from Roche, MSD, BMS and Bruker. A.S. is an employee at The Walter and Eliza Hall Institute, which receives milestone payments and royalties from Genentech and AbbVie for the development of Venetoclax. A.S. has collaborations with Servier for the development of MCL-1 inhibitors for cancer therapy. N.P. has had a consulting or advisory role for Novartis. C.S. has had a consulting or advisory role, received honoraria, research funding, and/or travel/accommodation expenses from: Pfizer, AstraZeneca, BMS, Roche Ventana, Boehringer Ingelheim, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, Illu-mina, Sarah Canon Research Institute, Genentech, Roche Ventana, GRAIL, Medicxi, and Dynamo Therapeutics. C.S. has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL. C.S. is co-founder and has stock options in Achilles Therapeutics. N.M. has stock options and has received consultancy fees from Achilles Therapeutics. P.J.J. has had a consulting or advisory role, received honoraria, research funding, and/or travel/accommodation expenses from: Abbvie, BMS, Boehringer, Novartis, Pfizer, Servier, and Celgene. All the other authors disclose no potential conflicts of interest. Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = sep,
day = "10",
doi = "10.1038/s41467-020-18372-1",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}