Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis

Duo Xu, Shun Qing Liang, Zhang Yang, Haitang Yang, Rémy Bruggmann, Simone Oberhaensli, Sabina Berezowska, Thomas M. Marti, Sean R.R. Hall, Patrick Dorn, Gregor J. Kocher, Ralph A. Schmid, Ren Wang Peng

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients’ tumors, we identified BCL-XL as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-XL-selective BH3 mimetic. Importantly, BCL-XL inhibition elicits protective autophagy, and concomitant blockade of BCL-XL and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease.

Original languageEnglish (US)
Article number406
JournalCell Death and Disease
Volume12
Issue number4
DOIs
StatePublished - Apr 2021
Externally publishedYes

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Publisher Copyright:
© 2021, The Author(s).

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