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.
Highlights
Medical or surgical castration remains the first line of systemic therapy for metastatic prostate cancer (PCa) since its discovery over 70 years ago [1]
We demonstrate that combination blockade of the AKT and MEK does improve responses compared to monotherapy in some of ourin in vitro and in vivo prostate cancer experiments
AZD5363 was found to induce a decrease in S6K phosphorylation in all cell lines; this effect was more pronounced in the PTEN null cells MR49C, MR49F, LNCaP and V16D cells compared to PTEN positive 22RV1 cells (Fig 1)
Summary
Medical or surgical castration remains the first line of systemic therapy for metastatic prostate cancer (PCa) since its discovery over 70 years ago [1]. The PI3K/AKT/mTOR and RAF/MEK/ERK signaling pathways play an important role in cell survival, treatment resistance, and cooperate to facilitate PCa progression to CRPC [4,5,6,7,8]. Both AKT [9, 10] and ERK [11, 12] signaling pathways are up-regulated with CRPC and are associated with poor outcome [13, 14]. The results vary considerably between model systems with the absence of additional benefit in some cases, highlighting the need to appropriately identify which patients will benefit most from a combination approach
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