Investigational serine/threonine kinase inhibitors against prostate cancer metastases

ABSTRACT

Introduction: Androgen deprivation therapy (ADT) is used as first therapeutic approach in prostate cancer (PCa) although castration resistant disease (CRPC) develops with high frequency. CRPC is the consequence of lack of apoptotic responses to ADT. Alternative targeting of the androgen axis with abiraterone and enzalutamide, as well as taxane-based chemotherapy were used in CRPC. Serine/threonine protein kinases (STKs) regulate different molecular pathways of normal and neoplastic cells and participate to development of CRPC as well as to the progression towards a bone metastatic disease (mCRPC).

Areas covered: The present review provide data on STK expression and activity in the development of CRPC as well as summarize recent reports of different strategies to block STK activity for the control of PCa progression.

Expert Opinion: Inhibitors for different STKs have been developed but clinical trials in PCa are comparatively rare and few exhibit satisfactory ‘drug-like’ properties. It is, however, necessary to intensify, when possible, the number of clinical trials with these drugs in order to insert new therapies or combinations with standard hormone- and chemo-therapies in the treatment guidelines of the mPCA.

KEYWORDS:

• Prostate cancer
• bone metastases
• serine threonine kinase
• EMT

Article highlights

• The first therapeutic approach in prostate cancer is the Androgen Deprivation Therapy (ADT).

• Castration resistant disease (CRPC) develops with high frequency after ADT as consequence of lack of apoptotic responses to ADT.

• Alternative AR targeting compounds as well as taxane-based chemotherapy are used as first line of therapy after CRPC.

• Serine/threonine protein kinases (STKs) regulate different molecular pathways of normal and neoplastic cells and participate to development of CRPC.

• Metastatic disease is often associated to activation of different STKs.

• Targeting of some STKs may represent as interesting therapeutic approach to slow-down the insurgence of CRPC and reduce development of metastatic lesions.

• STKs such as member of PI3K/Akt/mTOR or TGF-b pathways may be used to counteract bone metastases.

• It is, however, necessary to intensify, when possible, the number of clinical trials with these drugs in order to insert new therapies or combinations with standard hormone- and chemo-therapies in the treatment guidelines of the mCRPC disease.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded