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 whole wheat phyllo dough 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 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 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 here 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.