PI3 Kinase Pathway and MET Inhibition is Efficacious in Malignant Pleural Mesothelioma.
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.
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Rajani
R
Kanteti
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Jacob J
JJ
Riehm
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Immanuel
I
Dhanasingh
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Frances E
FE
Lennon
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Tamara
T
Mirzapoiazova
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Bolot
B
Mambetsariev
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Hedy L
HL
Kindler
Department of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.
Ravi
R
Salgia
D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D000631:Aminopyridines; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met