Combined blockade of activating ERBB2 mutations and ER results in synthetic lethality of ERþ/HER2 mutant breast cancer

Sarah Croessmann, Luigi Formisano, Lisa N. Kinch, Paula I. Gonzalez-Ericsson, Dhivya R. Sudhan, Rebecca J. Nagy, Aju Mathew, Eric H. Bernicker, Massimo Cristofanilli, Jie He, Richard E. Cutler, Alshad S. Lalani, Vincent A. Miller, Richard B. Lanman, Nick V Grishin, Carlos L Arteaga

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Purpose: We examined the role of ERBB2-activating mutations in endocrine therapy resistance in estrogen receptor positive (ERþ) breast cancer. Experimental Design: ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ERBB2 mutations in ERþ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis was used to determine the molecular interaction of HERL755S with HER3. Small molecules and siRNAs were used to inhibit PI3Ka, TORC1, and HER3. Results: Genomic data revealed a higher rate of ERBB2 mutations in metastatic versus primary ERþ tumors. MCF7 cells with isogenically incorporated ERBB2 kinase domain mutations exhibited resistance to estrogen deprivation and to fulvestrant both in vitro and in vivo, despite maintaining inhibition of ERa transcriptional activity. Addition of the irreversible HER2 tyrosine kinase inhibitor neratinib restored sensitivity to fulvestrant. HER2-mutant MCF7 cells expressed higher levels of p-HER3, p-AKT, and p-S6 than cells with wild-type HER2. Structural analysis of the HER2L755S variant implicated a more flexible active state, potentially allowing for enhanced dimerization with HER3. Treatment with a PI3Ka inhibitor, a TORC1 inhibitor or HER3 siRNA, but not a MEK inhibitor, restored sensitivity to fulvestrant and to estrogen deprivation. Inhibition of mutant HER2 or TORC1, when combined with fulvestrant, equipotently inhibited growth of MCF7/ERBB2V777L xenografts, suggesting a role for TORC1 in antiestrogen resistance induced by ERBB2 mutations. Conclusions: ERBB2 mutations hyperactivate the HER3/ PI3K/AKT/mTOR axis, leading to antiestrogen resistance in ERþ breast cancer. Dual blockade of the HER2 and ER pathways is required for the treatment of ERþ/HER2 mutant breast cancers.

Original languageEnglish (US)
Pages (from-to)277-289
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • General Medicine

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