MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma

Our plain-English summary of MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma, by R. Kanteti, I. Dhanasingh, I. Kawada, et al (PloS One, 2014).

The study

• Authors: R. Kanteti, I. Dhanasingh, I. Kawada, F.E. Lennon, Q. Arif, R. Bueno, R. Hasina, A.N. Husain, W. Vigneswaran, T. Seiwert, H.L. Kindler, R. Salgia
• Journal: PloS One
• Published: 2014;9(9):e105919
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.

In plain English

This was a laboratory study of malignant pleural mesothelioma (MPM). It did not study asbestos exposure and did not treat patients. The authors tested a MET inhibitor, ARQ 197, and two dual PI3K/mTOR inhibitors, NVP-BEZ235 and GDC-0980, alone and in combination. They used human mesothelioma cell lines and mice carrying tumors grown from the H2596 cell line, with 10 mice per group. They also stained an archived tissue array for p-AKT, a marker of PI3K activity. The text describes the array as 213 MPM and 196 normal lung samples, while the figure caption gives 212 and 192. p-AKT was higher in tumor tissue than in matched normal tissue. In cells, ARQ 197 combined with either PI3K/mTOR inhibitor acted synergistically in the H2596 and H513 lines. ARQ 197 alone slowed cell movement, and adding the other drugs gave no significant added benefit. In mice, GDC-0980 alone slowed tumor growth more than ARQ 197 alone. The combination slowed tumor growth more than any single drug (p less than 0.001), and those mice did not lose body weight. The authors concluded that the combination was promising and warrants further translational studies.

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: experiments in human mesothelioma cell lines and a mouse xenograft model, plus immunohistochemistry of archived tumor tissue microarrays
• Who was studied: Seven human mesothelioma cell lines plus one nonmalignant control line (Met-5A). An archived tissue microarray, described in the methods and results as 213 MPM and 196 normal lung samples; the Figure 1 caption gives 212 tumor and 192 normal lung samples. Female athymic nude mice carrying H2596 tumors, randomized into four groups of 10.
• Exposure: Drug treatments, not asbestos: the MET inhibitor ARQ 197 and the dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980, alone and combined. In mice: ARQ 197 200 mg/kg and GDC-0980 5 mg/kg, given once daily by oral gavage.
• Main results:
  • In archived samples, p-AKT expression was significantly greater in MPM tumor tissue than in matched normal tissue. PTEN expression showed no discernible difference.
  • In MPM cell lines, the drug concentration that halved cell viability (IC50) for ARQ 197 ranged from 0.1 to 0.4 micromolar. For the Met-5A control line it was about 8 micromolar.
  • ARQ 197 combined with GDC-0980 or with NVP-BEZ235 acted synergistically in the H2596 and H513 cell lines.
  • In H2596 and H513 cells, ARQ 197 alone significantly suppressed cell motility and delayed wound healing. Adding GDC-0980 or NVP-BEZ235 gave no significant advantage.
  • In H2596 cells, ARQ 197 arrested cells in the G2/M phase and the PI3K/mTOR inhibitors arrested cells in G0/G1. The combination mainly caused accumulation at G2/M.
  • In H2596 cells, ARQ 197 produced a four-fold increase in apoptosis (Annexin V staining). This almost doubled when ARQ 197 was combined with GDC-0980. The effect was not seen with NVP-BEZ235.
  • NVP-BEZ235 and GDC-0980 strongly suppressed AKT phosphorylation. ARQ 197 did not significantly affect it.
  • In mice with H2596 tumors, GDC-0980 alone slowed tumor growth far more than ARQ 197 alone.
  • In mice, ARQ 197 plus GDC-0980 suppressed tumor growth more than any single drug (p less than 0.001 in the text). Vehicle and ARQ 197 mice were sacrificed on day 19 because of tumor burden; the other groups were sacrificed on day 28.
  • Mice given ARQ 197 plus GDC-0980 did not lose body weight. The authors took this to suggest the combination was well tolerated.
• The authors' conclusion: The authors concluded that combined targeting of MET and PI3K/mTOR was advantageous in MPM cell lines and a mouse xenograft model. They judged the effect of ARQ 197/GDC-0980 on tumor growth in mice promising and said it warrants further translational studies.
• Limitations the authors state:
  • The authors noted that whether ARQ 197 specifically inhibits MET kinase activity is controversial.
  • The authors did not check autophagy in the cells treated with NVP-BEZ235 and ARQ 197.

Topics

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

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

Related studies

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• 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)
• Antitumor effect and antiangiogenic potential of the mTOR inhibitor temsirolimus against malignant pleural mesothelioma — M. Moriya, T. Yamada, et al. (2014)
• Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways — K. Shimazu, Y. Tada, et al. (2017)
• Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells — M. Bonelli, R. Terenziani, et al. (2020)

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