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Published on: May 27, 2021
Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast
Yiyu Dong1, Aimin Li, Jianbo Wang
1Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Abstract:
Basal-like breast cancers (BLBC) are highly aggressive, yet selective therapies targeting the specific oncoproteins driving these tumors have not been developed. These cancers frequently express epidermal growth factor receptor (EGFR), with resistance to its inhibition being well documented, albeit poorly understood. Notch pathway activation is also common in this breast cancer subtype and can be suppressed by gamma-secretase inhibitors, which effectively block receptor cleavage and activation. Herein, we show that although inhibition of either EGFR or Notch signaling alone is insufficient to suppress basal-like breast tumor cell survival and proliferation, simultaneous inhibition uncovers a synthetic lethal relationship between these two oncogenic pathways. This lethality is due in part to significant decreases in AKT activation caused by combined EGFR and Notch inhibition. Expression of the activated form of Notch1 restores AKT activity and enables cells to overcome cell death after dual-pathway blockade. Combined pathway inhibition is also dramatically more effective at suppressing tumor growth in mice than blocking EGFR or Notch signaling alone. Thus, we show that Notch pathway activation contributes to resistance to EGFR inhibition, and provide a novel treatment strategy for BLBCs.
Insights
Targeting both epidermal growth factor receptor (EGFR) and Notch signaling pathways simultaneously offers a novel synthetic lethal strategy to effectively treat aggressive basal-like breast cancers (BLBC). This combined approach overcomes resistance and suppresses tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Basal-like breast cancers (BLBC) are aggressive and lack targeted therapies.
- Epidermal growth factor receptor (EGFR) and Notch signaling are frequently activated in BLBC.
- Resistance to EGFR inhibition is a significant clinical challenge in BLBC.
Purpose of the Study:
- To investigate the therapeutic potential of simultaneously inhibiting EGFR and Notch signaling in BLBC.
- To elucidate the underlying mechanisms of combined pathway inhibition.
- To establish a novel treatment strategy for BLBC.
Main Methods:
- Inhibition of EGFR and Notch signaling pathways using specific inhibitors.
- Assessment of cell survival and proliferation.
- Analysis of AKT activation and downstream signaling.
- Evaluation of tumor growth in preclinical mouse models.
Main Results:
- Single-agent inhibition of EGFR or Notch was insufficient to suppress BLBC growth.
- Combined EGFR and Notch inhibition induced synthetic lethality in BLBC cells.
- Dual-pathway blockade significantly decreased AKT activation.
- Restoration of Notch1 activity rescued AKT activation and cell survival.
- Combined inhibition demonstrated superior tumor growth suppression compared to single-agent blockade.
Conclusions:
- Notch pathway activation contributes to resistance against EGFR inhibition in BLBC.
- Simultaneous inhibition of EGFR and Notch represents a promising synthetic lethal strategy for BLBC.
- This dual-targeting approach offers a novel therapeutic avenue for aggressive breast cancer subtypes.
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