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Effects of AKT/WEE1 inhibitors or ALDH inhibitor combined with PD-1 antibody on melanoma

ABSTRACT: The effects of AKT/WEE1 inhibitors or ALDH inhibitor combined with PD-1 antibody on melanoma were examined. Mouse B16F10 melanoma cells were subcutaneously injected into C57/B6 mice. When tumors were well-vascularized, mice were treated with anti-PD-1, AKT I (AZD5363)+WEE1 I (MK1775), AZD5363+MK1775+anti-PD-1, ALDH I (KS100), KS100+ anti-PD-1 daily. Mice were sacrificed when tumors in the control group (DMSO treated) reached 2000 mm3 and tumors were removed. RNA was extracted from tumor samples and gene expression was analized using RNAseq analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE199096 | GEO | 2023/12/31

REPOSITORIES: GEO

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Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling

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Effects of AKT/WEE1 inhibitors or ALDH inhibitor combined with PD-1 antibody on melanoma

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