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

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

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

Results: Genomic data revealed a higher rate of mutations in metastatic versus primary ER+ tumors. MCF7 cells with isogenically incorporated kinase domain mutations exhibited resistance to estrogen deprivation and to fulvestrant both and , despite maintaining inhibition of ERα 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 HER2 variant implicated a more flexible active state, potentially allowing for enhanced dimerization with HER3. Treatment with a PI3Kα 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/ xenografts, suggesting a role for TORC1 in antiestrogen resistance induced by mutations.

Conclusions: mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to antiestrogen resistance in ER+ breast cancer. Dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers.