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Cyclin dependent kinase 4 (CDK4); MEK; neuroblastoma Ras viral (v-Ras) oncogene (NRAS)

Mouse studies suggest combined inhibition of CDK4 and MEK could help treat NRAS-mutant melanomas. In an inducible mouse model of mutant Nras-driven melanoma, gene network analysis predicted that combined inhibition of CDK4 and MEK would mimic the loss of mutant NRAS expression. In the same mice, the MEK inhibitor trametinib and the CDK4 inhibitor PD-0332991 caused greater tumor growth inhibition than either compound alone. Next steps include evaluating the MEK and CDK4 inhibitor combination in patients with NRAS-mutant melanomas and identifying additional biomarkers that could help better determine whether a patient will respond to the combination therapy.
Trametinib, a small molecule inhibitor of MAP kinase kinase 1 (MAP2K1; MEK1) and MEK2 (MAP2K2) from Japan Tobacco Inc. and GlaxoSmithKline plc, is under review to treat melanoma.
Onyx Pharmaceuticals Inc. and Pfizer Inc. have PD-0332991, an oral small molecule CDK4 and CDK6 inhibitor, in Phase II testing or earlier to treat various cancers.

SciBX 5(38); doi:10.1038/scibx.2012.1000
Published online Sept. 27, 2012

Patent disclosure filed; available for licensing

Kwong, L.N. et al. Nat. Med.; published online Sept. 16, 2012;
Contact: Lynda Chin, The University of Texas MD Anderson Cancer Center, Houston, Texas