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Alterations of Epigenetic Modifications and 3D Genomic Architecture Drive Gene Expression Shifts in Primary Trastuzumab Resistance of HER2 Positive Breast Cancer

ABSTRACT: Primary trastuzumab resistance poses a significant challenge in the treatment of HER2-positive breast cancer. Despite various proposed mechanisms and responses to address this resistance, current treatments remain less effective, highlighting the need for new targets and insights. Our research, which integrates epigenomic and 3D genomic architectural data, suggests that changes in promoter modifications, specifically H3K4me3 and H3K27me3, along with differential active enhancers and promoter-enhancer interactions, may contribute to differential gene expression in trastuzumab-resistant versus sensitive cells. Notably, we identified SGK1, which lies downstream of both the PI3K-AKT and mTOR signaling pathways, exhibits overexpression associated with increased H3K4me3 signals at its promoter and enhanced promoter-enhancer interactions in trastuzumab-resistance cells. The overexpression of SGK1 supports cell survival and stimulates proliferation, making it a potential critical factor driving primary trastuzumab resistance. These discoveries provide new insights into the mechanisms underlying primary trastuzumab resistance in HER2-positive breast cancer, which may pave the way for developing more effective diagnostic and treatment strategies in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297715 | GEO | 2025/06/01

REPOSITORIES: GEO

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Alterations of Epigenetic Modifications and 3D Genomic Architecture Drive Gene Expression Shifts in Primary Trastuzumab Resistance of HER2 Positive Breast Cancer [RNA-seq]

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| phs001291 | dbGaP

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Project description:HER2 targeting with trastuzumab has changed the prognosis of breast cancer patients carrying amplification and/or overexpression of this oncogene. Despite this progress, however, resistance to trastuzumab occurs in the vast majority of patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show antitumor activity in a limited proportion of patients, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, due to the high proportion of patients that fail to respond to these alternative strategies, it is reasonable to assume that cells escaping HER2 targeting may rely on alternative pathways not involving HER2 to sustain their growth. Their knowledge is relevant for exploiting new therapies. To investigate this hypothesis we generated a human HER2 overexpressing breast cancer cell line resistant to trastuzumab and lapatinib (T100) and we have characterized it genetically and molecularly. In T100 cells, the previously proposed mechanisms of resistance to HER2 inhibitors did not explain cell escape. Notably, silencing HER2 by shRNA did not affect the growth of T100 cells, suggesting loss of reliance upon HER2. Among the alternative pathways that we explored, altered levels of the antiapoptoptic proteins Mcl-1 and Survivin were observed. This suggested the possibility of targeting resistant cells with the multitarget inhibitor sorafenib. Moreover, sorafenib, nearly inactive in parental cells, strongly inhibited the in vitro growth of T100 cells. In conclusion, we provide a new model where the activation of HER2 independent mechanisms sustains the growth of tumor cells, significantly increasing the sensitivity to sorafenib. Keywords: HER2, breast cancer, resistance, trastuzumab, lapatinib, sorafenib

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