Abl interconnects oncogenic Met and p53 core pathways in cancer cells

Flavio Maina (1) , Alessandro Furlan (1) , Filippo Conti (1) , Azeemudeen Hussain (1) , Sylvie Richelme (1) , Venturina Stagni (1) , Daniela Barilà (1) , Andrea Prodosmo (1) , Annarita Destro (1) , Massimo Roncalli (1)

1 IBDM - Institut de Biologie du Développement de Marseille

The simplicity of BCR-ABL "oncogene addiction" characterizing leukemia contrasts with the complexity of solid tumors where multiple "core pathways", including RTKs and p53, are often altered. This discrepancy illustrates the limited success of RTK antagonists in solid tumor treatment compared to 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 Ser392 and Mdm2 up-regulation. 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.

Mots clés: RTK signalling; c-Abl; HGF/Met; oncogenic signal; p53

Flavio Maina, Alessandro Furlan, Filippo Conti, Azeemudeen Hussain, Sylvie Richelme, et al.. Abl interconnects oncogenic Met and p53 core pathways in cancer cells. Cell Death and Differentiation, 2011, ⟨10.1038/cdd.2011.23⟩. ⟨hal-00628278⟩