Targeting AKT and PDK1 in Melanoma

MEERA SHAH; HYUNGSOO KIM; PABLO LOPEZ BERGAMI; SUPRIYA GAITONDE; SURYA DE; MARIANNA TCHERPAKOV; ANTIMONE DEWING; HONGBIN YUAN; MEGAN RIEL-MEHAN; STAN KRAJEWSKI; GAVIN ROBERTSON; MAURIZIO PELLECCHIA; ZE’EV RONAI

Boston

Congreso; Sixth International Melanoma Research Congress; 2009

Society for Melanoma Research

Background:  The Akt/PKB pathway plays a central role in tumor development and progression and is often upregulated in melanomas. Methods:  In silico screens for putative AKT inhibitors identified BI-69A11, a compound that was shown to inhibit AKT activity in in vitro kinase assays. Results:  UACC903 human melanoma cells, harboring PTEN mutation, treated with BI-69A11 caused efficient inhibition of Akt S473 phosphorylation but also reduced AKT protein expression, which coincided with inhibition of Akt association with HSP90. BI-69A11 treatment induced cell death of melanoma cell lines and its intra-peritoneal injection caused effective regression of melanoma tumors xenografts. Conclusion:  These findings identify BI-69A11 as a potent inhibitor of Akt signaling that is capable of eliciting effective regression of xenograft melanoma tumors. Background:  PDK1 is among the protein kinases implicated in the regulation of Akt. Results:  In recent studies we have identified that PDK1 transcription is regulated by c-Jun, which is commonly upregulated in melanoma bearing constitutively active ERK. Inhibition of c-Jun effectively attenuates melanoma growth, and such inhibition can be rescued by PDK1 in mouse xenografts. These findings prompted us to assess the possible effects of a PDK1 inhibitor – AR-12 – on melanoma in vitro and in vivo. Initial analysis revealed that AR-12 inhibited PDK1 activity and Akt phosphorylation. Administration of AR-12 to mice carrying melanoma xenografts attenuated tumor development. Conclusion:  These data provide initial support for the possible use of PDK1 as a target for melanoma development.