title: Cooperation between c-Met and focal adhesion kinase family members in medulloblastoma and implications for therapy.
abstract: We previously showed the involvement of the tyrosine kinase receptor c-Met in medulloblastoma malignancy. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and Pyk2 are key players in the progression of different cancers. However, their role in medulloblastoma malignancy is not well understood. In this study, using a protein array approach, we found that c-Met induces FAK and Pyk2 phosphorylation in medulloblastoma cells. We therefore studied the interactions between c-Met and FAK/Pyk2 and their implications for medulloblastoma therapy. We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines. We also found that FAK and Pyk2 mediate the malignant effects of c-Met on medulloblastoma cell proliferation, migration, and invasion. On the basis of these findings, we hypothesized that combined c-Met and FAK inhibitions would have additive effects on the inhibition of medulloblastoma malignancy. To test this hypothesis, we assessed the effects on medulloblastoma malignancy parameters of single or combined treatments of medulloblastoma cells with c-Met and FAK small-molecule kinase inhibitors. We found a significant increase in the inhibitory effect of both inhibitors on medulloblastoma cell migration and cell invasion as compared with single inhibitions (P < 0.05). In addition, oral gavage treatment with c-Met inhibitor of mice bearing medulloblastoma xenografts significantly reduced in vivo tumor growth. Therefore, combining c-Met inhibitors with FAK inhibitors constitutes a new potential strategy for medulloblastoma therapy. Altogether, our study describes a role for FAK and Pyk2 in medulloblastoma malignancy, uncovers new interactions between c-Met and FAK/Pyk2, and proposes for the first time combining anti-c-Met and anti-FAK inhibitors as a new strategy for medulloblastoma therapy.
authors.affiliation: Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Fadila
authors.initials: F
authors.lastname: Guessous
authors.forename: Yanzhi
authors.initials: Y
authors.lastname: Yang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Johnson
authors.forename: Lukasz
authors.initials: L
authors.lastname: Marcinkiewicz
authors.forename: Matthew
authors.initials: M
authors.lastname: Smith
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Alexander
authors.initials: A
authors.lastname: Kofman
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: James
authors.initials: J
authors.lastname: Christensen
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051418:Focal Adhesion Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D040081:Protein Array Analysis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D013450:Sulfones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: C521108:6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D015363:Quinolones; D013450:Sulfones; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; D051418:Focal Adhesion Kinase 2; C496050:PTK2 protein, human