Identification of a New Zytiga Resistance Pathway

A new resistance pathway to Zytiga therapy has emerged which involes signalling by the enzyme MAPK4 which is a MAP Kinase that upregulates androgen receptor (AR) expression and mediates tumour growth signalling via an androgen independant pathway. Hence hormone resistant prostate cancer is able to able to overcome total androgen blockade by Zytiga and continues growing by signals mediated by MAPK4. Therefore inhibitors of MAPK activity have potential to overcome Zytiga resistant prostate cancer (ZRPC) and should be considered as clinical candidates for use in combination with Zytiga, as well as for use in treating Zytiga relapsed patients.

MAPK4 is activated by phosphorylation by the enzyme p21 Activated Kinase (PAK) which is itself activated by the small GTP binding proteins p21 Rac and Rho. Thus the MAP4K signalling pathway proceeds along the route Rac-PAK-MAPK4-AR which offers several angles for therapeutic intervention by inhibition of Rac, PAK, or MAPK4 itself.

A selective inhibitor of MAPK4 has been identified called SB203580 but this has not been clinically tested. Pfizer have identified a potent inhibitor of PAK kinase with an IC50 of 1.3 nM, named PF-3758309. This drug shows exciting anticancer activity in pre-clinical models and is a drug candidate for human clinical trials. This has been a very well designed drug that snugly fits the cleft of the substrate binding pocket. Natural inhibitors of PAK kinase have been identified including propolis, resveratrol and salvestrol T30.

Molecular structure of PF-3758309 showing the (S) chiral phenyl substituent which fits precisely into the binding pocket.