Combined Blockade of Activating ERBB2 Mutations and ER Results in Synthetic Lethality of ER+/HER2 Mutant Breast Cancer.

ABSTRACT:

Purpose

We examined the role of ERBB2-activating mutations in endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer.

Experimental design

ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HER ^L755S with HER3. Small molecules and siRNAs were used to inhibit PI3Kα, TORC1, and HER3.

Results

Genomic data revealed a higher rate of ERBB2 mutations in metastatic versus primary ER+ tumors. MCF7 cells with isogenically incorporated ERBB2 kinase domain mutations exhibited resistance to estrogen

SUBMITTER: Croessmann S 

PROVIDER: S-EPMC6320312 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature