Serine/threonine protein kinases (STK) are interesting pharmacological targets for mCRPC being involved, inter alia, in resistance to therapy and local invasion or metastases. These protein family can be grouped in receptor STK and non-receptor STK.  Receptor belonging this class bind TGFβ/activin/nodal and BMP/GDF (growth/differentiation factor)/MIS (Müllerian inhibiting substance) and are involved in bone metastases. Bone marrow stromal cells, indeed, secreted TGF-β isoforms modulating apoptosis and malignant cells selection. This receptor activates a complex enzymatic cascade responsible for the promotion of Epithelial/Mesenchymal Transition (EMT) as well as to generation of cancer stem cells. Non receptor STKs include inter alia: (i) kinases of PI3K/Akt/mTOR pathway; (ii) Ras-RafMEK-ERK pathway pathway, (iii) Rho GTPases including p21 activated family members (PAK) including PAK proteins RhoA and C and Rho associated kinasaes (ROCKs). PI3K/AKT/mTOR and Ras-Raf-MEK-ERK signals are dysregulated in PCa. Hyperactive status of diverse signal-transduction pathways, such as the PI3K–AKT and MAPK pathways, or from alterations in the general nuclear import/export machinery may result in aberrant nucleocytoplasmic shuttling of proteins involved in cell proliferation and survival.

References

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