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

• Published in: Nature communications Vol. 11; no. 1; pp. 4527 - 13
• Main Authors: Munkhbaatar, Enkhtsetseg, Dietzen, Michelle, Agrawal, Deepti, Anton, Martina, Jesinghaus, Moritz, Boxberg, Melanie, Pfarr, Nicole, Bidola, Pidassa, Uhrig, Sebastian, Höckendorf, Ulrike, Meinhardt, Anna-Lena, Wahida, Adam, Heid, Irina, Braren, Rickmer, Mishra, Ritu, Warth, Arne, Muley, Thomas, Poh, Patrina S. P., Wang, Xin, Fröhling, Stefan, Steiger, Katja, Slotta-Huspenina, Julia, van Griensven, Martijn, Pfeiffer, Franz, Lange, Sebastian, Rad, Roland, Spella, Magda, Stathopoulos, Georgios T., Ruland, Jürgen, Bassermann, Florian, Weichert, Wilko, Strasser, Andreas, Branca, Caterina, Heikenwalder, Mathias, Swanton, Charles, McGranahan, Nicholas, Jost, Philipp J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.09.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/105; 13/106; 13/51; 14/32; 14/63; 38/23; 38/39; 631/67/1612/1350; 64/60; 692/4028/67/1612/1350; 96/95; Addictions; Adenocarcinoma; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Carcinoma, Non-Small-Cell Lung - diagnostic imaging; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell death; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Cell Survival - genetics; Clonal Evolution; Copy number; Datasets as Topic; Disease Models, Animal; Disease Progression; DNA Copy Number Variations; Evolutionary genetics; Gene deletion; High frequencies; Humanities and Social Sciences; Humans; Lung - diagnostic imaging; Lung - pathology; Lung cancer; Lung Neoplasms - diagnostic imaging; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mcl-1 protein; Mice; Mice, Transgenic; Molecular modelling; multidisciplinary; Mutation; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Non-small cell lung carcinoma; p53 Protein; Primary Cell Culture; Prospective Studies; Proto-Oncogene Proteins p21(ras) - genetics; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Retrospective Studies; RNA-Seq; Science; Science (multidisciplinary); Small cell lung carcinoma; Spheroids, Cellular; Survival; Therapeutic applications; Thiophenes - pharmacology; Thiophenes - therapeutic use; Tumor Burden - drug effects; Tumor Burden - genetics; Tumor Suppressor Protein p53 - genetics; Tumors; X-Ray Microtomography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18372-1

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. Cancer cells frequently harbour genetic aberrations that protect them from programmed cell death. Here, the authors show in non-small cell lung cancer that the anti-apoptotic gene MCL-1 is subject to copy number gains and that deletion of MCL-1 reduces tumour formation.