Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

Abstract

Despite recent improvements in patient outcomes using newer androgen receptor (AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer (CRPC) continues to remain a clinical problem. Co-targeting alternate resistance pathways are of significant interest to treat CRPC and delay the onset of resistance. Both the AKT and MEK signaling pathways become activated as prostate cancer develops resistance to AR-targeted therapies. This pre-clinical study explores co-targeting these pathways in AR-positive prostate cancer models. Using various in vitro models of prostate cancer disease states including androgen dependent (LNCaP), CRPC (V16D and 22RV1) and ENZ-resistant prostate cancer (MR49C and MR49F), we evaluate the relevance of targeting both AKT and MEK pathways. Our data reveal that AKT inhibition induces apoptosis and inhibits cell growth in PTEN null cell lines independently of their sensitivity to hormone therapy; however, AKT inhibition had no effect on the PTEN positive 22RV1 cell line. Interestingly, we found that MEK inhibition had greater effect on 22RV1 cells compared to LNCaP, V16D or ENZ-resistant cells MR49C and MR49F cells. In vitro, combination AKT and MEK blockade had evidence of synergy observed in some cell lines and assays, but this was not consistent across all results. In vivo, the combination of AKT and MEK inhibition resulted in more consistent tumor growth inhibition of MR49F xenografts and longer disease specific survival compared to AKT inhibitor monotherapy. As in our in vitro study, 22RV1 xenografts were more resistant to AKT inhibition while they were more sensitive to MEK inhibition. Our results suggest that targeting AKT and MEK in combination may be a valuable strategy in prostate cancer when both pathways are activated and further support the importance of characterizing the dominant oncogenic pathway in each patient's tumor in order to select optimal therapy.

The androgen receptor antagonist enzalutamide induces apoptosis, dysregulates the heat shock protein system, and diminishes the androgen receptor and estrogen receptor β1 expression in prostate cancer cells

“…Gene expression analysis has indicated that enzalutamide modulates the expression of factors involved in angiogenesis, cell adhesion, and apoptosis. 7 Using an in vitro enzalutamide-resistant PC model, Toren et al 8 observed that enzalutamide also activates the survival kinases protein kinase B (AKT) and mitogen-activated protein kinase kinase (MEK), as part of the enzalutamide resistance machinery.…”

Identification of Somatic Gene Signatures in Circulating Cell-Free DNA Associated with Disease Progression in Metastatic Prostate Cancer by a Novel Machine Learning Platform

“…Preclinical models have shown a compensatory relationship between PI3K and MAPK signaling in prostate cancer, 28 and that simultaneous inhibition of PI3K and MAPK signaling can inhibit mCRPC. [29][30][31] MAPK signaling can be targeted with MEK inhibitors, such as trametinib and cobimetinib, which are approved for BRAFmutated melanoma and KRAS/BRAF-mutated colorectal cancer. 32 Although anecdotal, a heavily pretreated mCRPC patient treated with trametinib elicited a durable clinical response.…”

Protocadherin 7 is overexpressed in castration resistant prostate cancer and promotes aberrant MEK and AKT signaling

“…Zhou et al observed that loss of function of PCDH7 significantly reduced tumor development, prolonged survival, and diminished phospho‐activation of ERK1/2 in lung cancer mouse model. Recent study by Torren et al shows reduced tumor growth of Enzalutamide resistant PCa cells by combined inhibition of AKT and ERK compared to monotherapy. Furthermore, these findings suggest that PCDH7 inhibition could diminish AKT and ERK activation and reveal future investigation of PCDH7 based therapeutics.…”