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Targeting the Notch signaling pathway and the Notch ligand, DLL3, in small cell lung cancer
Huan Zhang1, Yunkai Yang1, Xuchang Li1
1Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei, China.
Abstract:
Small cell lung cancer (SCLC) is a highly aggressive and poorly differentiated cancer with high-grade neuroendocrine (NE) features, accounting for approximately 15 % of all lung cancers. For decades, chemotherapy and radiotherapy have predominated the treatment strategy for SCLC, but relapses ensue quickly and result in poor survival of patients. Immunotherapy has brought novel insights, yet the efficacy is still restricted to a limited population with SCLC. Notch signaling is identified to play a key role in the initiation and development of SCLC, and the Notch ligand, Delta-like ligand 3 (DLL3) is found broadly and specifically expressed in SCLC cells. Thus, Notch signaling is under active exploration as a potential therapeutic target in SCLC. Herein, we summarized and updated the functional relevance of Notch signaling in SCLC, discussed Notch signaling-targeted therapy for SCLC and the correspondent preclinical and clinical trials, and investigated the promising synergy effects of Notch signaling targeted therapy and immune checkpoint inhibitors (ICIs) treatment.
Insights
Small cell lung cancer (SCLC) is aggressive, but Notch signaling, particularly DLL3, shows therapeutic promise. Targeting Notch signaling may improve SCLC treatment outcomes, potentially with immune checkpoint inhibitors.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer with poor patient survival.
- Current treatments like chemotherapy and radiotherapy have limited efficacy due to rapid relapse.
- Immunotherapy shows promise but benefits only a subset of SCLC patients.
Purpose of the Study:
- To review the role of Notch signaling in SCLC initiation and development.
- To discuss Notch signaling-targeted therapies and their clinical trials for SCLC.
- To explore the synergistic potential of Notch signaling inhibitors and immune checkpoint inhibitors (ICIs) in SCLC.
Main Methods:
- Literature review and synthesis of preclinical and clinical data.
- Analysis of Notch signaling pathway components, including DLL3.
- Investigation of combination therapy strategies.
Main Results:
- Notch signaling, specifically DLL3 expression, is crucial in SCLC.
- Targeting Notch signaling presents a viable therapeutic strategy for SCLC.
- Combination of Notch inhibitors and ICIs may enhance treatment efficacy.
Conclusions:
- Notch signaling is a key therapeutic target in SCLC.
- Targeted therapies against Notch signaling are under active investigation.
- Synergistic effects with ICIs offer a promising avenue for improving SCLC patient survival.
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