Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma

Our plain-English summary of Dynamic BH3 profiling identifies pro-apoptotic drug combinations for the treatment of malignant pleural mesothelioma, by D.S. Potter, R. Du, S.R. Bohl, et al (Nature Communications, 2023).

The study

• Authors: D.S. Potter, R. Du, S.R. Bohl, K.H. Chow, K.L. Ligon, R. Bueno, A. Letai
• Journal: Nature Communications
• Published: 2023;14(1):2897
• Cited by: 21 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) has relatively ineffective first/second-line therapy for advanced disease and only 18% five-year survival for early disease. Drug-induced mitochondrial priming measured by dynamic BH3 profiling identifies efficacious drugs in multiple disease settings. We use high throughput dynamic BH3 profiling (HTDBP) to identify drug combinations that prime primary MPM cells derived from patient tumors, which also prime patient derived xenograft (PDX) models. A navitoclax (BCL-xL/BCL-2/BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) combination demonstrates efficacy in vivo in an MPM PDX model, validating HTDBP as an approach to identify efficacious drug combinations. Mechanistic investigation reveals AZD8055 treatment decreases MCL-1 protein levels, increases BIM protein levels, and increases MPM mitochondrial dependence on BCL-xL, which is exploited by navitoclax. Navitoclax treatment increases dependency on MCL-1 and increases BIM protein levels. These findings demonstrate that HTDBP can be used as a functional precision medicine tool to rationally construct combination drug regimens in MPM and other cancers.

© 2023. The Author(s).

In plain English

This was a laboratory study of drug treatments for malignant pleural mesothelioma (MPM). It did not study asbestos exposure. The authors used high throughput dynamic BH3 profiling, a test of how close drug-treated cancer cells are to self-destruction (apoptosis). They screened clinically relevant drugs and drug pairs on cells from 13 freshly removed MPM tumors and on tumors grown in mice from three patient-derived models (two biphasic, one sarcomatoid). Navitoclax or S63845, combined with each other or with PI3K/AKT/mTOR pathway inhibitors, commonly scored as hits. Venetoclax did not. Seventy-nine percent of hits in the mouse-grown tumors were also hits in patient samples. All tumor-free mice given navitoclax plus S63845 died within 4 hours, so navitoclax plus AZD8055 was tested instead in mice carrying one tumor model. This combination reduced tumor volume compared with all other groups (p less than 0.0001). It also extended the time until tumors reached five times their starting volume, from day 19 in the vehicle group to day 49. Cell experiments suggested AZD8055 lowered MCL-1 and raised BIM. The authors concluded the method can identify effective drug combinations in MPM.

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 screening on fresh patient tumor cells outside the body (ex vivo), patient-derived xenograft (PDX) mouse experiments, and experiments in mesothelioma cell lines
• Who was studied: 13 freshly resected MPM patient tumors obtained under a Brigham and Women's Hospital / Dana-Farber Cancer Institute protocol (Boston). Three MPM PDX models, two biphasic (CPDM_0011x, CPDM_0106x) and one sarcomatoid (CPDM_0184x), grown in immunocompromised SCID-beige mice. Two epithelioid PDX models developed lymphoma. Four MPM cell lines (H2052, JMN, JMN1B, MSTO-211H). Collection dates are not given.
• Exposure: Asbestos exposure was not studied. The exposures were drug treatments: a screen of clinically relevant oncology drugs and combinations at 1 µM each, then in mice navitoclax 100 mg/kg, AZD8055 16 mg/kg, both together, or venetoclax 100 mg/kg, given daily for 21 days.
• Main results:
  • Across the patient samples, navitoclax and S63845, combined with one another or with a PI3K/AKT/mTOR pathway inhibitor, commonly primed MPM cells. Venetoclax did not.
  • Two tumors from the same patient (one adherent to the 7th rib, one from the pleura) gave correlated results (r = 0.74). 89 hits overlapped, with 104 hits in one tumor and 95 in the other.
  • Seventy-nine percent of the hits in the MPM PDX tumors were also hits in the MPM patient samples.
  • In a tolerance study in tumor-free mice, all mice given navitoclax plus S63845 died within 4 hours. Navitoclax plus AZD8055 was well tolerated.
  • In mice bearing CPDM_0011x tumors (vehicle n = 8, navitoclax n = 7, AZD8055 n = 7, combination n = 9, venetoclax n = 7), navitoclax plus AZD8055 reduced tumor volume compared with all other arms (p < 0.0001).
  • Survival was measured as time for tumors to reach five times their initial volume. With navitoclax plus AZD8055 it increased from day 19 (vehicle) to day 49 and was significantly longer than in every other arm (p < 0.0001).
  • AZD8055 alone decreased MCL-1 protein levels in CPDM_0011x PDX tumor cells but did not change the apoptosis markers cleaved PARP and cleaved caspase 3.
  • In all four MPM cell lines, the combination significantly reduced colony area and growth rate compared with either drug alone and with control.
• The authors' conclusion: The authors concluded that navitoclax plus AZD8055 was effective in the CPDM_0011x PDX model, which they said supports high throughput dynamic BH3 profiling as a way to identify effective drug combinations in MPM. They stated they hope to test this in a later clinical trial.
• Limitations the authors state:
  • There was only one sarcomatoid patient sample, so no comparison was made for that subtype.
  • No clinically significant genetic aberrations were found, so the authors could not say whether drug vulnerabilities are linked to such aberrations.
  • The authors expect responses to the combination to vary even among MPM patients.
  • The work relied on tissue from surgical resections, which may be more limited in other tumor types.

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, Second-Line Therapy.

Related studies

• Therapeutic Synergy in Esophageal Cancer and Mesothelioma Is Predicted by Dynamic BH3 Profiling — D.R. Surman, Y. Xu, et al. (2021)
• Network analysis of immunotherapy-induced regressing tumours identifies novel synergistic drug combinations — W.J. Lesterhuis, C. Rinaldi, et al. (2015)
• The flavonoid resveratrol suppresses growth of human malignant pleural mesothelioma cells through direct inhibition of specificity protein 1 — K.A. Lee, Y.J. Lee, et al. (2012)
• Manumycin A induces apoptosis in malignant pleural mesothelioma through regulation of Sp1 and activation of the mitochondria-related apoptotic pathway — K.H. Kim, J.I. Chae, et al. (2016)
• The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance — D. Barbone, J.A. Ryan, et al. (2011)
• Comparative Assessment and High-Throughput Drug-Combination Profiling of TEAD-Palmitoylation Inhibitors in Hippo Pathway Deficient Mesothelioma — L. Evsen, P.J. Morris, et al. (2023)

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