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

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

doi:10.1038/s41419-021-03668-x

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.

Highlights

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy that is etiologically associated with asbestos exposure[1,2]
In the attempt to explore the potential of B-cell lymphoma 2 (BCL-2) homology domain-3 (BH3) mimetics as anti-MPM therapy, we investigated genetic status, transcriptional expression, and dependency profile of the pro-survival BCL-2 gene family (BCL2L1, BCL2L10, BCL2, BCL2A1, BCL2L2, and MCL1) in MPM by interrogating the Cancer Genome Atlas (TCGA) dataset and functional genomics that determines genetic dependencies in cancers (DepMap; https://depmap.org/portal/)
XL for anti-apoptosis, and that neurofibromatosis type 2 (NF2)/large tumor suppressor kinase 1/2 (LATS1/2)-alterations and pro-apoptotic gene expression are associated with sensitivity to BCL-XL inhibition

Summary

Introduction

Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy that is etiologically associated with asbestos exposure[1,2]. The Hippo signaling, an evolutionally conserved pathway that regulates organ size and Official journal of the Cell Death Differentiation Association. Xu et al Cell Death and Disease (2021)12:406 tissue homeostasis by restricting cell growth and promoting apoptosis, is one of the best characterized Merlin/ NF2-regulated pathways[9]. Besides the mutation in NF2, other components of the Hippo pathway, e.g., large tumor suppressor kinase 1/2 (LATS1/2), are frequently inactivated in MPM patients[6]. Dysregulation of the Hippo pathway constitutively activates Yes-associated protein (YAP), a transcription regulator that promotes the transcription of genes involved in cell proliferation and antiapoptosis by interaction with TEA/ATTS domain (TEAD) transcription factors[10]

Methods

Results

Conclusion