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The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer [HiC]

ABSTRACT: Recent studies suggested that crosstalk between ERα and EGFR/HER2 pathways plays a critical role in mediating endocrine therapy resistance. Several targeting EGFR/HER2 signaling inhibitors including FDA-approved lapatinib and gefitinib as well as a novel dual tyrosine kinase inhibitor (TKI) sapitnib showed greater inhibitory efficacies. However, how a 3D chromatin landscape of the response to the inhibition to EGFR/HER2 pathway remains to be elucidated. In this study, we conducted in situ Hi-C and RNA-seq in two ERα+ breast cancer cell systems, tamoxifen-sensitive MCF7 and T47D and tamoxifen-resistant MCF7TR and T47DTR before and after the treatment of sapitnib. We identified differential response of topologically associated domains (TADs), looping genes and expressed genes. Interestingly, we found that many differential TADs and looping genes are reversible, indicating that EGFR/HER2 signaling may play a role in reshaping and rewiring the high order genome organization. We further examined and recapitulated the reversible looping genes in 3D spheroids of breast cancer cells. Our data provides a rich resource for further evaluating chromatin structural response to anti-EGFR/HER2 targeted therapies in endocrine-resistant breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144377 | GEO | 2020/12/01

REPOSITORIES: GEO

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Project description:Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to resensitize recurrent ERα (+) tumors to endocrine therapies. The objective of this study was to elucidate mechanisms of improved effectiveness of combined targeting of ERα and XPO1, a nuclear transport protein in overcoming endocrine resistance. Selinexor (SXR), an XPO1 antagonist, has been evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Using human phosphokinase array to profile kinase signaling pathways, we found that 4-OH Tamoxifen, SXR or their combination induced differential Akt phosphorylation profiles, changing the phosphorylation status and activity of the kinase. Also, our RNA sequencing data indicated that 4-OH Tamoxifen+SXR combination treatment causes gene expression changes distinct from 4-OH Tamoxifen and SXR treatments alone in tamoxifen-resistant cell lines. Since we observed dramatic changes in Akt activity and we saw a differential gene expression pattern with individual and combined 4-OH Tamoxifen and SXR treatments, we hypothesized that metabolic profile of breast cancer cells would change in the presence of 4-OH Tamoxifen and SXR. Using Seahorse metabolic profiler and cell viability experiments in limited media conditions, we showed that tamoxifen resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine as the mitochondrial fuel source. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodelling metabolic pathways to regenerate new vulnerabilities in endocrine resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role of ERα-XPO1 crosstalk plays in reducing cancer recurrences.

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The 3D Genomic Landscape of Differential Response to EGFR/HER2 Inhibition in Endocrine-Resistant Breast Cancer [HiC]

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