Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells

Our plain-English summary of Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells, by M. Bonelli, R. Terenziani, S. Zoppi, et al (International Journal of Molecular Sciences, 2020).

The study

• Authors: M. Bonelli, R. Terenziani, S. Zoppi, C. Fumarola, S. La Monica, D. Cretella, R. Alfieri, A. Cavazzoni, G. Digiacomo, M. Galetti, P.G. Petronini
• Journal: International Journal of Molecular Sciences
• Published: 2020;21(14)
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated to asbestos exposure. One of the most frequent genetic alteration in MPM patients is CDKN2A/ARF loss, leading to aberrant activation of the Rb pathway. In MPM cells, we previously demonstrated the therapeutic efficacy of targeting this signaling with the CDK4/6 inhibitor palbociclib in combination with PI3K/mTOR inhibitors. Here, we investigated whether such combination may have an impact on cell energy metabolism. Methods: The study was performed in MPM cells of different histotypes; metabolic analyses were conducted by measuring GLUT-1 expression and glucose uptake/consumption, and by SeaHorse technologies. Results: MPM cell models differed for their ability to adapt to metabolic stress conditions, such as glucose starvation and hypoxia. Independently of these differences, combined treatments with palbociclib and PI3K/mTOR inhibitors inhibited cell proliferation more efficaciously than single agents. The drugs alone reduced glucose uptake/consumption as well as glycolysis, and their combination further enhanced these effects under both normoxic and hypoxic conditions. Moreover, the drug combinations significantly impaired mitochondrial respiration as compared with individual treatments. These metabolic effects were mediated by the concomitant inhibition of Rb/E2F/c-myc and PI3K/AKT/mTOR signaling. Conclusions: Dual blockade of glycolysis and respiration contributes to the anti-tumor efficacy of palbociclib-PI3K/mTOR inhibitors combination.

In plain English

This was a laboratory study of human malignant pleural mesothelioma (MPM) cancer cells grown in culture. No patients or animals were studied, and asbestos exposure was not examined. The authors first compared four MPM cell lines of different histotypes. The lines differed in how they used energy and in how well they coped with glucose starvation and low oxygen (hypoxia). They then tested three drugs alone and as combinations with palbociclib: palbociclib itself, BEZ235 (which blocks both PI3K and mTOR) and BYL719 (which blocks the p110α subunit of PI3K). In 72-hour tests in H2052 cells, both combinations produced an additive inhibition of cell proliferation. In 24-hour tests in MSTO-211H and H2052 cells under normal oxygen, palbociclib or BEZ235 alone reduced glucose consumption by about 20%. The combinations reduced it by about 30% in MSTO-211H cells and 40% in H2052 cells. The combinations also reduced glycolysis (sugar breakdown) and mitochondrial respiration more than single drugs. The authors concluded that this supports their earlier suggestion that these combinations may be a valuable strategy for MPM treatment.

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 (in vitro) study in human malignant pleural mesothelioma cell lines
• Who was studied: Four commercially obtained human MPM cell lines: MSTO-211H (biphasic), H2452 and H28 (epithelioid), and H2052 (sarcomatoid). The drug and metabolism experiments used MSTO-211H and H2052 cells.
• Exposure: No asbestos exposure was studied. The drugs were palbociclib (a CDK4/6 inhibitor), BEZ235 (a dual PI3K and mTORC1-2 inhibitor) and BYL719 (a specific inhibitor of the p110α subunit of PI3K), alone and as combinations with palbociclib. The metabolic experiments used 24 h treatments with palbociclib 1 µM, BEZ235 40 nM and BYL719 (1 µM for MSTO-211H cells, 2.5 µM for H2052 cells), under normal oxygen or hypoxia (1% O2). The H2052 cell-proliferation experiments used 72 h treatments.
• Main results:
  • MSTO-211H cells depended heavily on glucose for growth, while H2052 cells were less sensitive to glucose deprivation.
  • Cell proliferation in H2052 cells was tested after 72 h of treatment with palbociclib 1 µM combined with increasing concentrations of BEZ235 (0.1 nM to 100 nM) or BYL719 (0.1 to 10 µM).
  • In H2052 cells, simultaneous treatment with palbociclib and BEZ235 or BYL719 produced an additive inhibition of cell proliferation.
  • In both MSTO-211H and H2052 cells, palbociclib combined with BEZ235 reduced glycolysis more than either drug alone.
  • Under normal oxygen, palbociclib or BEZ235 alone reduced glucose consumption by about 20%.
  • Under normal oxygen, palbociclib combined with either BEZ235 or BYL719 reduced glucose consumption by about 30% in MSTO-211H cells and about 40% in H2052 cells.
  • Under hypoxia, the drug combinations reduced glucose consumption by 30%, compared with 15–20% after single drugs.
  • In both cell lines, basal respiration, spare respiratory capacity and ATP production were strongly reduced after exposure to the drug combinations.
  • In H2052 cells, the combinations produced a stronger reduction of the c-myc protein.
• The authors' conclusion: The authors concluded that the study reinforces their earlier suggestion that palbociclib combined with PI3K/mTOR inhibitors (their shared term for BEZ235 and BYL719) may be a valuable therapeutic strategy for MPM.

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, Asbestos Exposure, CDKN2A, Hypoxia.

Related studies

• Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors — N. Echeverry, G. Ziltener, et al. (2015)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• PARP1 inhibition affects pleural mesothelioma cell viability and uncouples AKT/mTOR axis via SIRT1 — G. Pinton, A.G. Manente, et al. (2013)
• Combined Inhibition of NEDD8-Activating Enzyme and mTOR Suppresses NF2 Loss-Driven Tumorigenesis — J. Cooper, Q. Xu, et al. (2017)
• AKT/mTOR and c-Jun N-terminal kinase signaling pathways are required for chrysotile asbestos-induced autophagy — Z. Lin, T. Liu, et al. (2014)
• Transforming growth factor-β-induced protein (TGFBI) suppresses mesothelioma progression through the Akt/mTOR pathway — G. Wen, M. Hong, et al. (2011)

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