A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

A Targetable EGFR-Dependent Tumor-Initiating Program in Breast Cancer

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Summary: Therapies targeting epidermal growth factor receptor (EGFR) have variable and unpredictable responses in breast cancer.Screening triple-negative breast cancer (TNBC) patient-derived xenografts (PDXs), we identify a subset responsive to EGFR inhibition by gefitinib, which displays heterogeneous expression of wild-type EGFR.Deep single-cell RNA sequencing of 3,500 cells from an exceptional responder identified subpopulations displaying distinct biological features, where elevated EGFR expression was significantly enriched in a mesenchymal/stem-like cellular cluster.Sorted EGFRhi subpopulations exhibited enhanced stem-like features, including ALDH activity, sphere-forming efficiency, and tumorigenic and metastatic potential.

EGFRhi cells read more gave rise to EGFRhi and EGFRlo cells in primary and metastatic tumors, demonstrating an EGFR-dependent expansion and hierarchical state transition.Similar tumorigenic EGFRhi subpopulations were identified in pet calming peanut butter independent PDXs, where heterogeneous EGFR expression correlated with gefitinib sensitivity.This provides new understanding for an EGFR-dependent hierarchy in TNBC and for patient stratification for therapeutic intervention.: Savage et al.

demonstrate that sensitivity to EGFR inhibitor, gefitinib, in triple-negative breast cancer is paradoxically associated with EGFR heterogeneity.Using single-cell RNA sequencing in conjunction with functional assays, they identify TNBC tumors in which EGFR expression identifies cells with tumor-initiating capacity whose proliferative expansion is sensitive to EGFR inhibition.Keywords: breast cancer, tumor heterogeneity, patient-derived xenograft, single-cell RNA sequencing, EGFR inhibition, therapeutic response, tumor-initiating cell, cell hierarchy, BRCA1 mutation.