MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically

• DOI: 10.1038/s41467-020-18372-1
• Publication Date: 2020-09-10T10:05:20Z
• Authors: Enkhtsetseg Munkh...; Michelle Dietzen; Deepti Agrawal; Martina Anton; Moritz Jesinghaus; Melanie Boxberg; Nicole Pfarr; Pidassa Bidola; Sebastian Uhrig; Ulrike Höckendorf; Anna-Lena Meinhardt; Adam Wahida; Irina Heid; Rickmer Braren; Ritu Mishra; Arne Warth; Thomas Muley; Patrina S. P. Poh; Xin Wang; Stefan Fröhling; Katja Steiger; Julia Slotta-Husp...; Martijn van Grien...; Franz Pfeiffer; Sebastian Lange; Roland Rad; Magda Spella; Georgios T. Stath...; Jürgen Ruland; Florian Bassermann; Wilko Weichert; Andreas Strasser; Caterina Branca; Mathias Heikenwalder; Charles Swanton; Nicholas McGranahan; Philipp J. Jost
• Keywords: EXPRESSION; BCL-2 FAMILY; Lung Neoplasms; DNA Copy Number Variations; PROTEINS; Cell Survival; Science; Primary Cell Culture; 610; Datasets as Topic; Antineoplastic Agents; Apoptosis; Mice, Transgenic; MOUSE; LYMPHOCYTES; Article; Clonal Evolution; Mice; 03 medical and health sciences; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; KRAS; Animals; Humans; Prospective Studies; Lung; DOCETAXEL; 0303 health sciences; Q; CANCER; ddc:; 3. Good health; Disease Models, Animal; Mutation; SURVIVAL; Disease Progression; Myeloid Cell Leukemia Sequence 1 Protein; INHIBITORS; Non-small-cell lung cancer

AbstractEvasion 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.