2981 - Effect of Selumetinib plus AZD8186 treatment on Cabazitaxel sensitivity in docetaxel-acquired resistant metastatic prostate cancer cell lines

Background

PI3K/AKT/mTOR and MEK/ERK signalling pathways act cooperatively to develop taxane resistance in metastatic castration resistant prostate cancer (mCRPC). Inhibition of one of the pathways promotes a negative feedback that activates the other one. Co-inhibition of both pathways increases anti-tumor efficacy in preclinical models of PC. Our aim was to demonstrate whether combinations of Selumetinib (SELU; MEK inhibitor) + Capivasertib (CAPI; AKT inhibitor) or AZD8186 (PI3Kβ/δ inhibitor) could potentiate the effect of Cabazitaxel (CABA) treatment and revert resistance to Docetaxel (DOCE) in in vitro models.

Methods

The effect of drug treatments on the proliferation of DOCE-acquired resistant cells DU145-DR (PTEN WT/K-RAS MUT) and PC3-DR (PTEN Null/K-RAS WT) was determined by MTT assay and the median effect lines method; synergism was calculated using CompuSyn software. Phosphorylation status of AKT, ERK, GSK3β, S6 and p90RSK was analysed by Western Blot at basal level and after treatments.

Results

As compared to parental cells, p-AKT was significantly increased in DU145-DR and PC3-DR cells while p-ERK was increased in DU145-DR and decreased in PC3-DR. AZD8186 and CAPI alone showed little effect on DU145-DR cell viability (IC50>50µM). In contrast, both drugs decreased PC3-DR cell viability with IC50s of 0.5 and 1.5µM, respectively. SELU had no effect on proliferation of any cell line. SELU + CAPI and SELU + AZD8186 72h-concomitant treatment decreased DU145-DR proliferation in a highly synergistic manner, particularly the SELU + AZD8186 combination. Accordingly, this treatment was the more efficient in decreasing p-AKT and p-ERK. However, the addition of SELU didn’t enhance the efficacy of CAPI or AZD8186 in PC3-DR cells. SELU + AZD8186 promoted a dramatic increase of CABA and DOCE cytotoxicity in DU145-DR cells.

Conclusions

These results suggest that the combination of SELU + AZD8186 is highly synergistic at least in DU145-DR cells, leading to a very strong CABA sensitization and DOCE resistance reversion through the inhibition of AKT and ERK activation. Further experiments are ongoing in order to elucidate the role of these drugs in taxane sensitivity of PC3-DR and CABA-acquired resistant cells.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.