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

• DOI: 10.1038/s41419-021-03668-x
• Publication Date: 2021-04-15T10:30:49Z
• Authors: 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
• Keywords: Male; 0303 health sciences; QH573-671; Mesothelioma, Malignant; bcl-X Protein; 610 Medicine & health; Apoptosis; Mice, SCID; Article; 3. Good health; Mice; 03 medical and health sciences; Mice, Inbred NOD; Autophagy; 570 Life sciences; biology; Animals; Humans; Cytology

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