HER3 Differentiates Basal From Claudin Type Triple Negative Breast Cancer and Contributes to Drug and
Nicoleta Sinevici1, Bahar Ataeinia1, Veronica Zehnder1
1Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
Abstract:
Triple Negative Breast Cancer (TNBC) is an aggressive form of Breast Cancer (BC). Numerous kinase inhibitors (KI) targeting different pathway nodes have shown limited benefit in the clinical setting. In this study, we aim to characterize the extent of HER3 reliance and to define the effect of Neuregulin (NRG) isoforms in TNBCs. Basal and Claudin type TNBC cell lines were treated with a range of small molecule inhibitors, in the presence or absence of the HER3 ligand NRG. Single agent and combination therapy was also evaluated in human cancer cell lines through viability and biochemical assessment of the AKT/MAPK signaling pathway. We show that Basal (BT20, HCC-70, and MDA-MB-468) and Claudin type (MDA-MB-231, BT-549) TNBC cell lines displayed differential reliance on the HER family of receptors. Expression and dynamic HER3 upregulation was predominant in the Basal TNBC subtype. Furthermore, the presence of the natural ligand NRG showed potent signaling through the HER3-AKT pathway, significantly diminishing the efficacy of the AKT and PI3K inhibitors tested. We report that NRG augments the HER3 feedback mechanism for continued cell survival in TNBC. We demonstrate that combination strategies to effectively block the EGFR-HER3-AKT pathway are necessary to overcome compensatory mechanisms to NRG dependent and independent resistance mechanisms. Our findings suggests that the EGFR-HER3 heterodimer forms a major signaling hub and is a key player in tumorigenesis in Basal but not Claudin type TNBC tested. Thus, HER3 could potentially serve as a biomarker for identifying patients in which targeted therapy against the EGFR-HER3-AKT axis would be most valuable.
Insights
Triple Negative Breast Cancer (TNBC) shows varied reliance on HER3 signaling. Neuregulin (NRG) enhances HER3 activity, necessitating combination therapies targeting the EGFR-HER3-AKT pathway for effective treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Triple Negative Breast Cancer (TNBC) is an aggressive subtype with limited treatment options.
- Kinase inhibitors have shown minimal clinical benefit in TNBC.
- Understanding HER3 receptor signaling is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of HER3 signaling and Neuregulin (NRG) isoforms in TNBC.
- To characterize differential HER3 reliance in Basal and Claudin TNBC subtypes.
- To evaluate the efficacy of combination therapies targeting the HER3-AKT pathway.
Main Methods:
- Treatment of TNBC cell lines (Basal and Claudin types) with small molecule inhibitors and NRG.
- Assessment of cell viability and AKT/MAPK signaling pathway.
- Evaluation of single-agent and combination therapy responses.
Main Results:
- Basal and Claudin TNBC cell lines exhibit distinct HER family receptor dependencies.
- HER3 expression and upregulation are prominent in Basal TNBC.
- NRG potentiates HER3-AKT signaling, reducing the efficacy of AKT and PI3K inhibitors.
- NRG augments HER3 feedback, promoting cell survival and resistance.
Conclusions:
- Combination therapies blocking the EGFR-HER3-AKT pathway are essential to overcome resistance mechanisms in TNBC.
- The EGFR-HER3 heterodimer is a significant signaling hub in Basal TNBC tumorigenesis.
- HER3 may serve as a biomarker for identifying patients who would benefit from targeted EGFR-HER3-AKT therapy.
