title: Abl interconnects oncogenic Met and p53 core pathways in cancer cells.
abstract: The simplicity of BCR-ABL 'oncogene addiction' characterizing leukemia contrasts with the complexity of solid tumors where multiple 'core pathways', including receptor tyrosine kinases (RTKs) and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared with the impact of Imatinib in BCR-ABL-dependent leukemia. Here, we identified c-Abl as a signaling node interconnecting Met-RTK and p53 core pathways, and showed that its inhibition impairs Met-dependent tumorigenesis. Met ensures cell survival through a new path in which c-Abl and p38-MAPK are employed to elicit p53 phosphorylation on Ser(392) and Mdm2 upregulation. We found a clinical correlation between activated Met, phospho-p53, and Mdm2 levels in human tumors, supporting the role of this path in tumorigenesis. Our findings introduce the concept that RTK-driven tumors may be therapeutically treated by hitting signaling nodes interconnecting core pathways. Moreover, they underline the importance of evaluating the relevance of c-Abl antagonists for combined therapies, based on the tumor signaling signature.
authors: Developmental Biology Institute of Marseille-Luminy (IBDML), UMR 6216, CNRS - Inserm - Université de la Méditerranée, Campus de Luminy-Case 907, 13288 Marseille Cedex 9, France.
authors: A
authors: A
authors: Furlan
authors: V
authors: V
authors: Stagni
authors: A
authors: A
authors: Hussain
authors: S
authors: S
authors: Richelme
authors: F
authors: F
authors: Conti
authors: A
authors: A
authors: Prodosmo
authors: A
authors: A
authors: Destro
authors: M
authors: M
authors: Roncalli
authors: D
authors: D
authors: Barilà
authors: F
authors: F
authors: Maina
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D056945:Hep G2 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use; D011485:Protein Binding; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D000068877:Imatinib Mesylate; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D016315:Proto-Oncogene Proteins c-abl; D048051:p38 Mitogen-Activated Protein Kinases