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. 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 HERL755S 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 vs. primary ER+ 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 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 HER2L755S 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/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 ER+ breast cancer. Dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers. Translational Significance ERBB2 activating mutations occur with increased frequency in ER+ breast cancers after progression on antiestrogen therapy. Inhibition of mutant HER2 function with neratinib restores the efficacy of antiestrogen therapy. Thus, we propose dual blockade of the HER2 and ER pathways is required for the treatment of ER+/HER2 mutant breast cancers.

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…Remarkably, hotspot mutations in PIK3CA are frequent in ER+BCs, which account for up to 80% of BCs, and Her2 mutations hyperactivate the HER3/ PI3K/AKT/mTOR axis, leading to anti-ER resistance in ER+BCs. Hence, dual blockade of the Her2 and ER pathways is necessary for the treatment of ER+/Her2 mutant BCs [168]. Moreover, PIK3CA and MAP3K1 alterations reveal Luminal A status in ER+ metastatic BCs and the patients are likely to clinically benefit from BKM120 [169].…”

Efficacy and Determinants of Response to HER Kinase Inhibition inHER2-Mutant Metastatic Breast Cancer

“…In addition to its role in breast cancer initiation, HER2 signaling activation has been identified as a mechanism of endocrine therapy resistance (4,(12)(13)(14)(15)(16)(17). Moreover, feedback between HER2 and estrogen receptor (ER) signaling has been postulated to be reciprocal, such that inhibition of either pathway may result in upregulation and activation of the other (18,19).…”

“…Moreover, feedback between HER2 and estrogen receptor (ER) signaling has been postulated to be reciprocal, such that inhibition of either pathway may result in upregulation and activation of the other (18,19). Indeed, treatment with neratinib induces ER-dependent gene transcription in HER2-positive (HER2 + ) breast cancer cell lines (20,21) and has been demonstrated to overcome endocrine resistance in HER2-mutant breast cancer cell lines and xenografts (14,17). Consistent with these observations, the greatest benefit of neratinib as extended adjuvant therapy in HER2 + breast cancer in the ExteNET trial was in the ER-positive (ER + ) subgroup, most of whom were receiving concurrent endocrine therapy (22).…”

Acquired FGFR and FGF alterations confer resistance to estrogen receptor (ER) targeted therapy in ER+ metastatic breast cancer

“…Although various resistance mechanisms have been proposed for tamoxifen and aromatase inhibitor resistance, including loss or modification in ER expression ( ESR1 activating mutations and ESR1 fusions) [3–7], and regulation of alternative signal transduction pathways (PI3K/AKT/mTOR and EGFR/ERBB2/MAPK) [8–10], mechanisms of resistance to SERDs remain understudied. Mechanisms of endocrine resistance identified in patients include acquired mutations in the estrogen receptor itself [4–7], acquired activating mutations in ERBB2 (HER2) [11, 12], loss of function of NF1 [13], and other alterations in MAPK pathway genes [14]. Additional mechanisms remain to be identified.…”