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Effect of MK-8931 on GSC gene expression

ABSTRACT: Glioblastoma (GBM), contains different tumor-associated macrophage (TAM) populations that can either promote tumor growth and therapeutic resistance (pTAMs) or have tumor suppressive properties (sTAMs), and thus reprograming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small molecule compounds we find that inhibition of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization through trans-IL-6-sIL-6R-STAT3 signaling. MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease in clinical trials, and have been shown to be safe for humans, these could be potentially streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181649 | GEO | 2021/08/26

REPOSITORIES: GEO

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Project description:Introduction: Mammalian target of rapamycin (mTOR) represents a key downstream intermediate for a myriad of oncogenic receptor tyrosine kinases. In the case of the insulin-like growth factor (IGF) pathway, the mTOR complex (mTORC1) mediates IGF-1 receptor (IGF-1R)-induced estrogen receptor alpha (ERÎ±) phosphorylation/activation and leads to increased proliferation and growth in breast cancer cells. As a result, the prevalence of mTOR inhibitors combined with hormonal therapy has increased in recent years. Conversely, activated mTORC1 provides negative feedback regulation of IGF signaling via insulin receptor substrate (IRS)-1/2 serine phosphorylation and subsequent proteasomal degradation. Thus, the IGF pathway may provide escape (e.g. de novo or acquired resistance) from mTORC1 inhibitors. It is therefore plausible that combined inhibition of mTORC1 and IGF-1R for select subsets of ER-positive breast cancer patients presents as a viable therapeutic option. Methods: Using hormone-sensitive breast cancer cells stably transfected with the aromatase gene (MCF-7/AC-1), works presented herein describe the in vitro and in vivo antitumor efficacy of the following compounds: dalotuzumab (DALO; âMK-0646â; anti-IGF-1R antibody), ridaforolimus (RIDA; âMK-8669â; mTORC1 small molecule inhibitor) and letrozole (âLETâ, aromatase inhibitor). Results: With the exception of MK-0646, all single agent and combination treatment arms effectively inhibited xenograft tumor growth, albeit to varying degrees. Correlative tissue analyses revealed MK-0646 alone and in combination with LET induced insulin receptor alpha A (InsR-A) isoform upregulation (both mRNA and protein expression), thereby further supporting a triple therapy approach. Conclusion: These data provide preclinical rationalization towards the combined triple therapy of LET plus MK-0646 plus MK-8669 as an efficacious anti-tumor strategy for ER-positive breast tumors. 46 samples, 28 days post treatment

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Effect of MK-8931 on GSC gene expression

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