PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma

Our plain-English summary of PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma, by R. Kanteti, J.J. Riehm, I. Dhanasingh, et al (Scientific Reports, 2016).

The study

• Authors: R. Kanteti, J.J. Riehm, I. Dhanasingh, F.E. Lennon, T. Mirzapoiazova, B. Mambetsariev, H.L. Kindler, R. Salgia
• Journal: Scientific Reports
• Published: 2016;6:32992
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is commonly associated with prior asbestos exposure. Receptor tyrosine kinases (RTKs) such as MET and its downstream target PI3K are overexpressed and activated in a majority of MPMs. Here, we studied the combinatorial therapeutic efficacy of the MET/ALK inhibitor crizotinib, with either a pan-class I PI3K inhibitor, BKM120, or with a PI3K/mTOR dual inhibitor, GDC-0980, in mesothelioma. Cell viability results showed that MPM cells were highly sensitive to crizotinib, BKM120 and GDC-0980 when used individually and their combination was more effective in suppressing growth. Treatment of MPM cells with these inhibitors also significantly decreased cell migration, and the combination of them was synergistic. Treatment with BKM120 alone or in combination with crizotinib induced G2-M arrest and apoptosis. Both crizotinib and BKM120 strongly inhibited the activity of MET and PI3K as evidenced by the decreased phosphorylation of MET, AKT and ribosomal S6 kinase. Using a PDX mouse model, we showed that a combination of crizotinib with BKM120 was highly synergetic in inhibiting MPM tumor growth. In conclusion our findings suggest that dual inhibition of PI3K and MET pathway is an effective strategy in treating MPM as compared to a single agent.

In plain English

This was a laboratory study; it did not study patients or asbestos exposure. The authors tested crizotinib, a drug that blocks a protein called MET, alone and with BKM120 or GDC-0980, drugs that block a signaling pathway called PI3K. They used human malignant pleural mesothelioma cell lines and a patient's mesothelioma tumor grown in female nude mice. Most mesothelioma cell lines were sensitive to BKM120. The drug combinations were reported as synergistic (stronger together than expected) in suppressing cell growth. Crizotinib plus BKM120 reduced colony formation more than either drug alone. Its effects on cell migration and on cell death were not statistically significantly greater than BKM120 alone. In the mice, tumor volumes at day 17 with crizotinib alone or BKM120 alone were not significantly different from vehicle-treated controls. The combination group had significantly lower tumor volumes, but that group also showed increased morbidity, and the experiment ended on day 17. The authors concluded that dual MET/PI3K targeting showed potential for treating malignant pleural mesothelioma.

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 using human mesothelioma cell lines (in vitro) and a patient-derived tumor xenograft (PDX) mouse model (animal experiment)
• Who was studied: Human mesothelioma cell lines (H2596, H513, H2461, H2052, H2452, H28, H2373) and a benign transformed mesothelial control line (Met-5A), obtained from the American Type Culture Collection. Also female nude mice aged 5 to 8 weeks implanted with a human mesothelioma patient tumor (CTG-0234). The number of mice is not given.
• Exposure: No asbestos exposure was studied. The exposures were the drugs crizotinib (MET/ALK inhibitor), BKM120 (pan-class I PI3K inhibitor) and GDC-0980 (PI3K/mTOR inhibitor), alone and in combination. Mice received daily oral doses of vehicle, crizotinib 25 mg/kg, BKM120 10 mg/kg, or the combination.
• Main results:
  • Most mesothelioma cell lines were sensitive to BKM120, with IC50 values (the concentration halving viability) from 0.79 to 1.51 micromolar.
  • The Met-5A control mesothelial cell line and the H28 line were less sensitive to BKM120.
  • In H2596 cells, the crizotinib plus BKM120 combination gave a combination index of 0.08. A value below 1 indicates synergy.
  • In H2596 cells, the crizotinib plus GDC-0980 combination gave a combination index of 0.63.
  • In cell migration tests, the BKM120 plus crizotinib combination reduced migration more than BKM120 alone, but the difference was not statistically significant.
  • In H2596 cells, crizotinib, BKM120 and GDC-0980 given alone had no effect on G2-M cell cycle arrest.
  • In H2596 cells, crizotinib alone gave a 2.5-fold increase in apoptotic (dying) cells.
  • The crizotinib plus BKM120 combination did not give a statistically significant increase in apoptotic cells compared with BKM120 alone.
  • In a soft agar test, BKM120 plus crizotinib significantly reduced the number of H2596 colonies compared with either drug alone.
  • In the mouse PDX model at day 17, tumor volumes in the crizotinib-alone and BKM120-alone groups were not significantly different from the vehicle control group.
  • In the mouse PDX model, the crizotinib plus BKM120 group had significantly lower tumor volumes.
  • The combination-treated mice showed increased morbidity without significant body weight changes, and the experiment was stopped on day 17.
• The authors' conclusion: The authors concluded that their results demonstrate the potential of dual MET/PI3K targeting for treating malignant pleural mesothelioma. They also stated that patients would likely benefit from combination treatments.

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, Asbestos Exposure, Mesothelioma, Apoptosis.

Related studies

• Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors — N. Echeverry, G. Ziltener, et al. (2015)
• Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma — W.B. Ou, C. Hubert, et al. (2011)
• Inhibition of activated phosphatidylinositol 3-kinase/AKT pathway in malignant pleural mesothelioma leads to G1 cell cycle arrest — I. Mikami, F. Zhang, et al. (2010)
• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy — B. Fischer, C. Frei, et al. (2012)
• Coactivation of receptor tyrosine kinases in malignant mesothelioma as a rationale for combination targeted therapy — M. Brevet, S. Shimizu, et al. (2011)

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