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

Our plain-English summary of Malignant pleural mesothelioma co-opts BCL-XL and autophagy to escape apoptosis, by D. Xu, S.Q. Liang, Z. Yang, et al (Cell Death & Disease, 2021).

The study

• Authors: D. Xu, S.Q. Liang, Z. Yang, H. Yang, R. Bruggmann, S. Oberhaensli, S. Berezowska, T.M. Marti, S.R.R. Hall, P. Dorn, G.J. Kocher, R.A. Schmid, R.W. Peng
• Journal: Cell Death & Disease
• Published: 2021;12(4):406
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study of malignant pleural mesothelioma (MPM). It did not study asbestos exposure. The authors analysed public genetic and protein databases, including a TCGA group of 87 MPM patients. They tested human MPM cell lines against normal mesothelial cells (LP-9) and treated mice carrying MESO-1 tumor grafts. In one database covering 32 cancer types, MPM had the third highest level of the survival protein BCL-XL. Blocking BCL-XL with the drug A-1155463 inhibited growth more in MPM cells than in LP-9 cells. In MESO-1 cells, doses of 62.5, 125 and 250 nM gave 4-, 4.4- and 5.4-fold increases in apoptotic (dying) cells compared with vehicle treatment. MPM cells with NF2/LATS1/2 gene alterations were more sensitive to the drug. Blocking BCL-XL also increased autophagy, a cell self-recycling process, in MPM cells but not in LP-9 cells. Adding hydroxychloroquine, an autophagy blocker, produced strong synergy in cells. In mice (5 per group), adding it improved tumor control without obvious body weight loss. The authors concluded that their data suggest therapeutic potential. Mouse groups were randomized but not blinded.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study combining analysis of public cancer databases, experiments on human cell lines, and a mouse xenograft (tumor graft) treatment experiment
• Who was studied: Human MPM cell lines (MESO-1, MESO-4, JL-1, H2452, MSTO-211H, H2052, and H28 in some experiments). Comparison cells were normal mesothelial cells (LP-9) and normal lung fibroblasts. Database analyses included a TCGA cohort of 87 MPM patients. The animal experiment used 8-week-old male NSG mice, 5 per treatment group, with MESO-1 tumors grown under the skin.
• Exposure: No asbestos exposure was studied. The exposures were treatments: the BCL-XL inhibitor A-1155463, BCL2L1 gene knockdown, and the autophagy inhibitor hydroxychloroquine (HCQ). In mice the doses were A-1155463 at 5 mg/kg and HCQ at 50 mg/kg, each injected once daily, for 23 days.
• Main results:
  • In the TCPA protein dataset of 32 cancer types, mesothelioma had the third highest level of BCL-XL.
  • A-1155463 caused significantly greater growth inhibition in MPM cells than in normal LP-9 mesothelial cells.
  • In MESO-1 cells, A-1155463 at 62.5, 125 and 250 nM produced 4-, 4.4- and 5.4-fold increases in apoptotic cells compared with vehicle. In LP-9 cells, apoptosis barely increased.
  • NF2/LATS1/2 loss of function was found in 38% of the TCGA MPM cohort. MPM cell lines with these alterations were more sensitive to A-1155463.
  • BCL-XL inhibition increased autophagy markers in MPM cells; the same effects were not seen in LP-9 cells.
  • In MPM cell lines, A-1155463 combined with HCQ produced strong synergy. This held for both NF2/LATS1/2-mutant and wild-type cells, but not for normal lung fibroblasts.
  • In mice with MESO-1 tumors, A-1155463 alone delayed tumor growth. Adding HCQ further enhanced antitumor efficacy without obvious body weight loss.
• The authors' conclusion: The authors concluded that their data suggest therapeutic potential for targeting BCL-XL alone in subsets of MPM, and for also targeting autophagy in unselected MPM.
• Limitations the authors state:
  • The mouse sample size was not set by statistical calculation, and group allocation was randomized but not blinded.
  • The authors noted that changes in SQSTM1/p62 can be context-dependent and need cautious interpretation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis.

Related studies

• Increased sensitivity to apoptosis upon endoplasmic reticulum stress-induced activation of the unfolded protein response in chemotherapy-resistant malignant pleural mesothelioma — D. Xu, S.Q. Liang, et al. (2018)
• The novel BH3 α-helix mimetic JY-1-106 induces apoptosis in a subset of cancer cells (lung cancer, colon cancer and mesothelioma) by disrupting Bcl-xL and Mcl-1 protein-protein interactions with Bak — X. Cao, J.L. Yap, et al. (2013)
• CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma — D. Xu, S.Q. Liang, et al. (2020)
• Knockdown of Bcl-xL enhances growth-inhibiting and apoptosis-inducing effects of resveratrol and clofarabine in malignant mesothelioma H-2452 cells — Y.J. Lee, I.S. Hwang, et al. (2014)
• Cisplatin and resveratrol induce apoptosis and autophagy following oxidative stress in malignant mesothelioma cells — Y.J. Lee, G.J. Lee, et al. (2016)
• Pro-oxidant activity of sulforaphane and cisplatin potentiates apoptosis and simultaneously promotes autophagy in malignant mesothelioma cells — Y.J. Lee, S.H. Lee (2017)

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