Abstract 2981
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.
Resources from the same session
2115 - Preclinical in vivo screening to predict responder patients depend on EGFR status
Presenter: Yejin Kim
Session: Poster Display session 3
Resources:
Abstract
3349 - Interplay between miR-17-5p and MALAT-1 Shapes The Cytokine Storm in Triple Negative Breast Cancer (TNBC) Tumor Microenvironment
Presenter: Raghda Soliman
Session: Poster Display session 3
Resources:
Abstract
4014 - Clinical verification on the relationship between lipid metabolism and the immune microenvironment of breast cancer
Presenter: Wataru Goto
Session: Poster Display session 3
Resources:
Abstract
4158 - The clinical and transcriptional signatures of human CD204 reveal an applicable marker for tumor associated macrophage in breast cancer
Presenter: Yunjie He
Session: Poster Display session 3
Resources:
Abstract
5392 - Activated effector T cells co-expressing multiple inhibitory receptors (IRs) are enriched in the tumor immune microenvironment in high grade serous ovarian cancer (HGSOC)
Presenter: Alice Bergamini
Session: Poster Display session 3
Resources:
Abstract
2617 - Oncolytic reovirus as a new anti-tumor strategy in castration resistant prostate cancer
Presenter: Yunlim Kim
Session: Poster Display session 3
Resources:
Abstract
2995 - Dysregulation of helper T lymphocytes in esophageal squamous cell carcinoma (ESCC) patients is highly associated with aberrant production of miR-21
Presenter: Ali Memarian
Session: Poster Display session 3
Resources:
Abstract
3597 - Myeloid derived suppressor cells but not regulatory T cells are associated with adaptive immunity and clinical outcomes in anal squamous cell carcinoma
Presenter: Christophe Borg
Session: Poster Display session 3
Resources:
Abstract
3430 - Evaluation of immune responses among responders (R) and non-responders (non-R) in a humanized mouse model with colorectal cancer (CRC) xenografts treated with combination immunotherapy
Presenter: Juan Marín Jiménez
Session: Poster Display session 3
Resources:
Abstract
1995 - ¬¬Advanced melanoma patients with high CD16+ macrophages have better response and survival to anti-PD-1 based immunotherapy
Presenter: Hansol Lee
Session: Poster Display session 3
Resources:
Abstract