BCL-XL is an actionable target for treatment of malignant pleural mesothelioma

Our plain-English summary of BCL-XL is an actionable target for treatment of malignant pleural mesothelioma, by S. Arulananda, M. O'Brien, M. Evangelista, et al (Cell Death Discovery, 2020).

The study

• Authors: S. Arulananda, M. O'Brien, M. Evangelista, T.J. Harris, N.S. Steinohrt, L.J. Jenkins, M. Walkiewicz, R.J.J. O'Donoghue, A.R. Poh, B. Thapa, D.S. Williams, T. Leong, J.M. Mariadason, X. Li, J. Cebon, E.F. Lee, T. John, W.D. Fairlie
• Journal: Cell Death Discovery
• Published: 2020;6(1):114
• Cited by: 18 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.

In plain English

This laboratory study, not a study of asbestos exposure, tested BH3-mimetics, drugs that block proteins helping cancer cells avoid dying. It used malignant pleural mesothelioma (MPM) cell lines and mice grafted with one MPM cell line (MSTO-211H). The authors also measured these proteins in tumour samples from 326 Australian patients, collected 2000 to 2010. In cell lines, BCL-XL blockers killed most lines potently, while blocking only BCL-2 or MCL-1 did little; blocking BCL-XL and MCL-1 together was synergistic. In mice, the BCL-XL blocker A-1331852 gave tumour control similar to Cisplatin, though it was given almost daily and Cisplatin only once. With survival measured as time until a tumour reached 1000 mm3, when mice were culled, the combination gave a median of 39 days, versus 26 for either drug alone and 20 for controls. In patients, high BCL-XL showed a non-significant trend toward shorter survival. High BCL-2, seen in few samples, was linked to significantly shorter survival. The authors concluded that BCL-XL inhibition showed encouraging activity. They noted the mouse studies used one cell line.

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: drug tests on human MPM cell lines, mouse xenograft experiments, and analysis of protein levels and survival in a patient tumour tissue microarray
• Who was studied: Human MPM cell lines (one, 14R-100, derived from an Austin Hospital patient); female NOD-scid mice given MSTO-211H tumour grafts (8 to 10 per group); tumour samples from 326 patients diagnosed with MPM at the Austin Hospital, Victoria, Australia, between 1 January 2000 and 31 December 2010
• Exposure: No asbestos exposure was studied. The treatments tested were BH3-mimetic drugs: ABT-263 (Navitoclax), ABT-199 (Venetoclax), A-1331852 and S63845, alone and combined with each other or with Cisplatin. In mice, A-1331852 (25 mg/kg) or ABT-263 (100 mg/kg) was given by mouth, and Cisplatin (4 mg/kg) was given as a single injection. Genetic deletion of MCL-1 in tumour cells was also tested.
• Main results:
  • In MPM cell lines, A-1331852 (which targets BCL-XL) killed most lines potently (EC50 below 50 nM), while all lines were relatively resistant to ABT-199 and S63845 (EC50 above 10 μM)
  • In cell lines, combining ABT-263 or A-1331852 with the MCL-1 inhibitor S63845 lowered EC50 values by up to 100-fold, and these responses were synergistic
  • In cell lines, adding ABT-263 or A-1331852 increased the potency of Cisplatin in most MPM lines
  • In mice, A-1331852 and Cisplatin each gave similar tumour growth control and survival compared with controls (A-1331852 was given almost daily, Cisplatin as a single dose)
  • In the mouse experiments, survival was measured as time until the tumour reached 1000 mm3, the ethical endpoint at which mice were culled, not time until natural death
  • In mice, the combination of A-1331852 and Cisplatin gave a median survival (time to the 1000 mm3 tumour endpoint) of 39 days, versus 26 days for either drug alone (p < 0.01) and 20 days for controls (p < 0.01)
  • Mice given A-1331852 had significantly reduced platelets 24 hours after dosing; platelet counts returned to normal within a week of stopping treatment
  • In mice, BCL-XL inhibition combined with genetic deletion of MCL-1 in the tumour cells doubled survival time compared with controls
  • In the 326-patient cohort, patients whose tumours had high BCL-XL showed a non-significant trend toward shorter overall survival (11.8 versus 16.8 months; HR 1.36, 95% CI 0.99 to 1.86, p = 0.057)
  • In the patient cohort, patients whose tumours had high BCL-2 had significantly shorter overall survival (9.1 versus 12.8 months; HR 1.63, 95% CI 1.02 to 2.61, p = 0.038), though high BCL-2 was seen in only a small percentage of samples
• The authors' conclusion: The authors concluded that blocking BCL-XL and MCL-1 together was the most effective way to kill MPM cells. In their view, BCL-XL inhibition alone had encouraging activity and made cells more sensitive to Cisplatin, and BCL-XL remains an actionable target for MPM treatment.
• Limitations the authors state:
  • The mouse studies used a single cell line
  • In mice, the BH3-mimetics were given almost daily, but Cisplatin was given only once, which affects the comparison between them
  • Tumours in the combination experiments did not shrink, suggesting that some cells within the tumours remained highly resistant to treatment

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Pemetrexed (Alimta), Chemotherapy.

Related studies

• A novel BH3-mimetic, AZD0466, targeting BCL-XL and BCL-2 is effective in pre-clinical models of malignant pleural mesothelioma — S. Arulananda, M. O'Brien, et al. (2021)
• Malignant Pleural Mesothelioma: From Pathophysiology to Innovative Actionable Targets — F.R. Bertuccio, S. Montini, et al. (2025)
• Glutathione S-transferase P1-1 as a target for mesothelioma treatment — A. De Luca, F. Pellizzari Tregno, et al. (2013)
• Molecular targets in malignant pleural mesothelioma treatment — G. Pasello, A. Favaretto (2009)
• Role of iron in inactivation of epidermal growth factor receptor after asbestos treatment of human lung and pleural target cells — A. Baldys, A.E. Aust (2005)
• Novel approaches for the treatment of unresectable malignant pleural mesothelioma: A focus on immunotherapy and target therapy (Review) — E. Rijavec, F. Biello, et al. (2022)

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