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Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
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What for patients with NRG1 fusions? Looking into Pandora's box
Domenico Trombetta1, Antonio Rossi2, Marco Donatello Delcuratolo3
1Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy.
Abstract:
Neuregulin 1 is a small ligand that interacts with HER2-4 receptors, activating downstream signaling pathways strictly linked to cell survival and proliferation. In some cancers, NRG1 gene is fused with other genes, leading to constitutive activation of the HER signaling and promoting tumorigenesis. Cancers with NRG1 fusions may benefit from pharmacological inhibition using agents that can specifically target either the ligand (NRG1) or the receptor (HER3/HER4), thereby offering a novel personalized approach to therapy by interfering with the growth of cancer cells that depend on this signaling pathway. Multiple strategies are employed to achieve ever-increasing efficacy of the newly proposed therapies, including combination therapies with other targeted approaches, small compounds, and monoclonal antibodies. This narrative review summarizes the available data on the spectrum of all available drugs targeting NRG1/HER deregulation in cancers with NRG1 fusions, their chemistry, pharmacodynamics, pharmacokinetics, and metabolism, as well as the clinical efficacy in NRG1-positive patients.
Insights
Neuregulin 1 (NRG1) fusions drive cancer by activating HER signaling. Therapies targeting NRG1 or HER receptors offer personalized treatment options for these specific cancer types.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Neuregulin 1 (NRG1) is a ligand activating HER2-4 receptors, crucial for cell survival and proliferation.
- NRG1 gene fusions in cancer lead to constitutive HER signaling activation, promoting tumorigenesis.
Purpose of the Study:
- To review current therapeutic strategies targeting NRG1/HER deregulation in cancers with NRG1 fusions.
- To summarize drug efficacy, chemistry, pharmacodynamics, pharmacokinetics, and metabolism of agents targeting NRG1-positive cancers.
Main Methods:
- Narrative review of existing scientific literature.
- Analysis of data on drugs targeting NRG1/HER pathway in NRG1-fusion-positive cancers.
Main Results:
- NRG1 fusions represent a targetable mechanism in specific cancers.
- Pharmacological inhibition of NRG1 ligand or HER3/HER4 receptors offers personalized therapeutic avenues.
- Combination therapies with small compounds and monoclonal antibodies enhance treatment efficacy.
Conclusions:
- Targeting NRG1/HER deregulation provides a novel personalized approach for NRG1-fusion-positive cancers.
- Understanding drug profiles is essential for optimizing treatment strategies.
- Further research into combination therapies can improve clinical outcomes.
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