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

Enkhtsetseg Munkhbaatar; 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-Huspenina; Martijn van Griensven; Franz Pfeiffer; Sebastian Lange; Roland Rad; Magda Spella; Georgios T. Stathopoulos; Jürgen Ruland; Florian Bassermann; Wilko Weichert; Andreas Strasser; Caterina Branca; Mathias Heikenwalder; Charles Swanton; Nicholas McGranahan; Philipp J. Jost

doi:10.1038/s41467-020-18372-1

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

Enkhtsetseg Munkhbaatar
, 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-Huspenina, Martijn van Griensven, Franz Pfeiffer, Sebastian Lange, Roland Rad, Magda Spella, Georgios T. Stathopoulos, Jürgen Ruland, Florian Bassermann, Wilko Weichert, Andreas Strasser, Caterina Branca, Mathias Heikenwalder, Charles Swanton, Nicholas McGranahan, Philipp J. Jost

Technical University of Munich
University College London
Lincoln's Inn Fields Laboratory
German Cancer Research Center
Heidelberg University
Universitätsklinikum Heidelberg
Institute of Pathology
Thoraxklinik at the University Hospital Heidelberg
member of the German Centre for lung Research (DZL)
Charité – Universitätsmedizin Berlin
University of Maastricht
University of Patras
Helmholtz Zentrum München German Research Center for Environmental Health
and University of Melbourne Department of Medical Biology and School of Mathematics and Statistics
University of Melbourne
Medical University of Graz

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

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.

Original language	English
Article number	4527
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18372-1
State	Published - 1 Dec 2020

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SDG 3 Good Health and Well-being

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10.1038/s41467-020-18372-1

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Munkhbaatar, E., Dietzen, M., Agrawal, D., Anton, M., Jesinghaus, M., Boxberg, M., Pfarr, N., Bidola, P., Uhrig, S., Höckendorf, U., Meinhardt, A. L., Wahida, A., Heid, I., Braren, R., Mishra, R., Warth, A., Muley, T., Poh, P. S. P., Wang, X., ... Jost, P. J. (2020). MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. Nature Communications, 11(1), Article 4527. https://doi.org/10.1038/s41467-020-18372-1

@article{4598ed2949c44a20b5b0fa6fa69dc4fe,

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.",

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 Meinhardt, \{Anna Lena\} 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 = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-18372-1",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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Munkhbaatar, E, Dietzen, M, Agrawal, D, Anton, M, Jesinghaus, M, Boxberg, M, Pfarr, N, Bidola, P, Uhrig, S, Höckendorf, U, Meinhardt, AL, Wahida, A, Heid, I, Braren, R, Mishra, R, Warth, A, Muley, T, Poh, PSP, Wang, X, Fröhling, S, Steiger, K, Slotta-Huspenina, J, van Griensven, M , Pfeiffer, F, Lange, S, Rad, R, Spella, M, Stathopoulos, GT, Ruland, J, Bassermann, F , Weichert, W, Strasser, A, Branca, C, Heikenwalder, M, Swanton, C, McGranahan, N & Jost, PJ 2020, 'MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically', Nature Communications, vol. 11, no. 1, 4527. https://doi.org/10.1038/s41467-020-18372-1

TY - JOUR

T1 - MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically

AU - Munkhbaatar, Enkhtsetseg

AU - Dietzen, Michelle

AU - Agrawal, Deepti

AU - Anton, Martina

AU - Jesinghaus, Moritz

AU - Boxberg, Melanie

AU - Pfarr, Nicole

AU - Bidola, Pidassa

AU - Uhrig, Sebastian

AU - Höckendorf, Ulrike

AU - Meinhardt, Anna Lena

AU - Wahida, Adam

AU - Heid, Irina

AU - Braren, Rickmer

AU - Mishra, Ritu

AU - Warth, Arne

AU - Muley, Thomas

AU - Poh, Patrina S.P.

AU - Wang, Xin

AU - Fröhling, Stefan

AU - Steiger, Katja

AU - Slotta-Huspenina, Julia

AU - van Griensven, Martijn

AU - Pfeiffer, Franz

AU - Lange, Sebastian

AU - Rad, Roland

AU - Spella, Magda

AU - Stathopoulos, Georgios T.

AU - Ruland, Jürgen

AU - Bassermann, Florian

AU - Weichert, Wilko

AU - Strasser, Andreas

AU - Branca, Caterina

AU - Heikenwalder, Mathias

AU - Swanton, Charles

AU - McGranahan, Nicholas

AU - Jost, Philipp J.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85090501561

U2 - 10.1038/s41467-020-18372-1

DO - 10.1038/s41467-020-18372-1

M3 - Article

C2 - 32913197

AN - SCOPUS:85090501561

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4527

ER -

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

Abstract

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