Co-targeting driver pathways in prostate cancer: two birds with one stone.

Amina Zoubeidi,Martin E Gleave

doi:10.15252/emmm.201808928

Abstract

Co‐targeting strategies strive to improve cancer outcomes by combining therapies under contextualized genetic and environmental conditions that selectively target exploitable alterations in tumor cells. Adaptive survival pathways triggered by inhibition of driver genes in the androgen receptor (AR) or PI3K/AKT pathways are of great interest, since they are among the most frequently altered in castrate‐resistant prostate cancer (CRPC). Unfortunately, negative feedback loops exist between the AR and PI3K/AKT pathways such that targeting AR leads to activation of PI3K/AKT signaling, while PI3K/AKT pathway inhibition leads to increased AR transcriptional activity. Hence, targeting both pathways provides an opportunity for conditional lethality and a high therapeutic index. In this issue of EMBO Molecular Medicine , Yan et al (2018) present an elegant study showing that histone deacetylase 3 (HDAC3) acts as a common upstream activator of both AR and AKT signaling pathways, and use HDAC3 inhibitors as a monotherapy to co‐target two major pathways driving CRPC growth.

Highlights

Co-targeting strategies strive to improve cancer outcomes by combining therapies under contextualized genetic and environmental conditions that selectively target exploitable alterations in tumor cells
There is a need to develop more active regimens, either by combining currently approved drugs, or via design of novel biologically rational regimens to create contextual lethality based on genomic biomarker enrichment, and/or co-targeting adaptive survival pathways activated by androgen receptor (AR) pathway inhibitors
While clinical responses are common with AR pathway inhibitors, responses using PI3K inhibitors are rare in preclinical models or patients with castrateresistant prostate cancer (CRPC)

Summary

Introduction

Co-targeting strategies strive to improve cancer outcomes by combining therapies under contextualized genetic and environmental conditions that selectively target exploitable alterations in tumor cells. The discovery that castration-resistant prostate cancer (CRPC) most often remains fueled by androgen receptor (AR) signaling ushered in the development and clinical integration of highly potent AR pathway inhibitors. The AR (via amplification, mutation, variants) and PI3K/AKT (via Pten loss) pathways are the two most frequently genomically altered pathways in CRPC.

Results

Conclusion