Table 1 Preclinical data in breast cancer cell lines and xenografts.
Article | ER-targeting agent | HER2-targeting agent | Models used | Key summaries |
|---|---|---|---|---|
In vitro studies | ||||
Rusnak 200141 | None | GW2016 (Lapatinib;TKI) | Activity in ERBB2− overexpressing cell lines, including breast cancer cell line (BT474) | Lapatinib inhibited tumor xenograft growth of BT474 cells at doses of 30 and 100 mg/kg, with complete inhibition at the higher dose |
Xia 200642 | Fulvestrant (SERD) | Lapatinib (TKI) | Acquired resistance to lapatinib in ERBB2 (HER2)-overexpressing/ER+ breast cancer cell line (BT474) | Acquired resistance to lapatinib was mediated by a switch to ER and HER2 codependence rather than loss of HER2 expression or insensitivity of HER2 signaling to lapatinib Treatment with fulvestrant plus lapatinib effectively prevented the outgrowth of viable resistant cells |
Cavaliere 201046 | Formestane (anti-aromatase) | Trastuzumab (mAb) | CD44+/CD24-low breast cancer cells from epithelial-mesenchymal co-cultures of human breast cancer tissue | Treatment with trastuzumab, formestane, or formestane + trastuzumab were associated with 16% (P < 0.01), 25% (P < 0.01), and 50% (P < 0.001) inhibition of cell growth, respectively Cell growth inhibition correlated with decreased levels of cyclin D1 |
Chan 201747 | Endoxifen (non-steroidal SERM) | Lapatinib (TKI) | Panel of breast cancer cell models of ERα/HER2 crosstalk that exhibiting either a priori ERα/HER2 crosstalk (BT474) or acquired ERα/HER2 crosstalk (TAM-R, MCF-7/HER2) | Synergistic anticancer effects for lapatinib plus endoxifen were observed in all models of ERα/HER2 crosstalk |
Collins 201748 | Fulvestrant (SERD) | Pertuzumab (mAb), lumretuzumab (mAb) | Human ER+/HER2-low breast cancer cell line (MCF-7) | Lumretuzumab and pertuzumab were both potent inhibitors of HER2/HER3 signaling in MCF-7 cells when administered as single agents |
Li 201549 | Fulvestrant (SERD) | Lapatinib (TKI) | Acquired resistance to lapatinib in breast cancer cells (BT474) | In lapatinib-resistant BT474 cells, significant inhibition of PI3K/Akt pathway and activation of MAPK and ER pathways were detected Cell growth was markedly suppressed by the lapatinib plus fulvestrant |
McDermott 201750 | Tamoxifen (SERM) | Trastuzumab (mAb) | Models of HER2+/ER+/IGF-1R+ breast cancer (MCF7, BT474, MDA-MB-361, HCC1419) | Dual blockade of ER and IGF-1R enhanced growth inhibition in all 4 HER2+ cell lines and increased cell cycle arrest in G1 in BT474 cells Enhanced responses were also observed when trastuzumab + tamoxifen was combined with an IGF-1R TKI Acquired resistance to trastuzumab may be overcome by tamoxifen plus an IGF-1R TKI |
Croessmann 201823 | Fulvestrant (SERD) | Neratinib (TKI) | ER+ MCF-7 breast cancer cells with isogenically incorporated ERBB2 kinase domain mutations | Resistance to estrogen deprivation and fulvestrant were observed The combination of fulvestrant and neratinib was associated with potent inhibition of fulvestrant-resistant breast cancer cells that harbor ERBB2 kinase missense mutations |
Sudhan 201851 | Fulvestrant (SERD) | Neratinib (TKI) | ER+/HER+ breast cancer cell lines (BT474, MDA-MB-361, and UACC-893) | The combination of neratinib + fulvestrant was associated with inhibition of ER/HER2 crosstalk and ER+/HER2+ breast cancer cell growth |
Ribas 201853 | Fulvestrant (SERD) Tamoxifen (SERM) | Neratinib (TKI) | Panel of ER+ breast cancer cell lines adapted to long-term estrogen deprivation, expressing wild-type or mutant ESR1, and modeling acquired resistance to an AI | Concentration-dependent decreases in proliferation were observed with neratinib or everolimus alone, irrespective of ESR1 mutation status Combination therapy with neratinib plus endocrine therapy or everolimus plus endocrine therapy further reduced proliferation, but the maximal inhibitory effect was observed with the triple combination of neratinib + everolimus + endocrine therapy |
Nayar 201954 | Fulvestrant (SERD) | Neratinib (TKI) | ER+/HER2+ breast cancer cell lines (MCF-7 and T47D) transfected with constructs encoding various ERBB2 mutants or controls | ERBB2 mutations conferred estrogen independence and resistance to tamoxifen, fulvestrant, and palbociclib Neratinib overcame endocrine resistance in ERBB2-mutant, ER+ breast cancer cell lines and provided enhanced tumor growth inhibition when combined with fulvestrant |
Shagisultanova 201955 | Fulvestrant (SERD) | Tucatinib (TKI) | HR+/HER2+ breast cancer cell lines (BT474, MDA-MB-361, and UACC-812) | The combination of fulvestrant, tucatinib, and palbociclib was active in all 3 cell lines; addition of fulvestrant to tucatinib + palbociclib improved the activity of the doublet Tucatinib and its doublet and triplet combinations suppressed downstream effector phERK1/2 in BT474; only doublet and triplet combinations were effective in MDA-MB-361 |
In vivo studies | ||||
Scaltriti 201652 | g (SERD) | Neratinib (TKI) | Cell-based and patient-derived ER+, HER2-driven xenograft models | Neratinib plus fulvestrant significantly inhibited tumor growth and prolonged survival in tumor-bearing mice, compared with single-agent or control treatments |
Collins 201748 | Fulvestrant (SERD) | Pertuzumab (mAb), lumretuzumab (mAb) | Mouse xenograft model of ER+/HER2-low/HER3+ human breast cancer (HBCx-19) | Treatment with single-agent lumretuzumab and pertuzumab induced tumor stasis (100% RTV) and partial regression (60% RTV) Pertuzumab + lumretuzumab was associated with strong tumor regression (10% RTV) Triple combination therapy with pertuzumab + lumretuzumab + fulvestrant was the most efficacious treatment, inducing long-lasting tumor regression |
Li 201549 | Fulvestrant (SERD) | Lapatinib (TKI) | BT474 xenograft model of acquired resistance to lapatinib | Combination therapy with lapatinib + fulvestrant was associated with a significantly greater reduction in tumor volume, compared with either agent alone |
Croessmann 201823 | Fulvestrant (SERD) | Neratinib (TKI) | Xenograft models of ERBB2 mutant breast cancer (mice injected with MCF-7 cells harboring ERBB2 mutations) | ERBB2 mutations hyperactivate the HER3/PI3K/Akt/mTOR axis, leading to anti-estrogen resistance in ER+ breast cancer cells Treatment with neratinib + fulvestrant restored sensitivity to fulvestrant; dual blockade of HER2 and ER pathways was needed for treatment of ER+/ERBB2 mutant breast cancers |
Sudhan 201851 | Fulvestrant (SERD) | Neratinib (TKI) | ER+/HER2+ xenograft models of breast cancer (mice injected with MDA-MB-361 cells) | Extended adjuvant therapy with fulvestrant + neratinib maintained complete responses, whereas fulvestrant alone resulted in rapid relapse |
Ribas 201853 | Fulvestrant (SERD) Tamoxifen (SERM) | Neratinib (TKI) | Xenograft model of resistance to AI therapy (BLAB/c FOX nude mice injected with MCF-2a-long-term estrogen deprivation cells) | Triple combination with neratinib + everolimus + fulvestrant was the most effective treatment for reducing tumor volume |
