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.
Highlights
Receptor tyrosine kinases (RTKs) are known to play a crucial role in tumor growth and metastasis
We have studied the role of MET and it’s downstream signaling targets Phosphatidylinositol 3-kinase (PI3K)/mTOR in Malignant pleural mesothelioma (MPM) and showed that a combinatorial approach to suppress both MET and PI3K activities is more effective than targeting individual pathways
In general combined treatment with MET inhibitor, crizotinib, and PI3K inhibitors, BKM120 or GDC-0980 resulted in a synergistic suppression of MPM cell growth
Summary
RTKs are known to play a crucial role in tumor growth and metastasis. Some RTKs were originally discovered as oncogenes and are known to provide key signals that lead to transformation, tumor growth and metastasis[9]. Treatment of H2596 cells with the combination of crizotinib and BKM120 further decreased PI3K activity as compared to single drug or vehicle treated cells. GDC-0980, the dual PI3K/mTOR inhibitor had no discernable effect on the level of PIP3, but the combination with crizotinib significantly decreased the activity of PI3K as compared to single drug or vehicle treated cells.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
