ArticleOncogene2022
Oncogenic KRAS promotes growth of lung cancer cells expressing SLC3A2-NRG1 fusion via ADAM17-mediated shedding of NRG1.
Article in Oncogene, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 25 citations in OpenAlex.
- Structure, mechanism and clinical relevance of NRG1 fusions in cancer.Journal of biomedical science · 2026Review
- Solute Carrier transporters in tumor metabolism and immune modulation: implications for therapy.Journal of translational medicine · 2026Review
- Evaluating the implications of K-Ras, KEAP1/NRF2-mediated signaling pathways and metabolic alterations in urethane-induced lung cancer.Journal of molecular histology · 2026Article
- Article
- ADAM Proteases in Cancer: Biological Roles, Therapeutic Challenges, and Emerging Opportunities.Cancers · 2025Review
- Oncogenic Fusions in NSCLC: From Mechanisms to Clinical Applications.International journal of molecular sciences · 2025Review
- Examining the contribution of Notch signaling to lung disease development.Naunyn-Schmiedeberg's archives of pharmacology · 2024Review
- Review
- Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy.Molecular metabolism · 2024Review
- Review
- Next-Generation Sequencing in Lung Cancers-A Single-Center Experience in Taiwan.Medicina (Kaunas, Lithuania) · 2024Article
- Analysis on the pathogenesis and treatment progress of NRG1 fusion-positive non-small cell lung cancer.Frontiers in oncology · 2024Review
- Clinicopathological Characteristics of NRG1 Fusion-Positive Solid Tumors in Korean Patients.Cancer research and treatment · 2023Review
- The Therapeutic Landscape forCancers · 2023Review
- KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration.Journal of clinical medicine · 2023Review
- Article
- Immunomodulatory role of metalloproteinase ADAM17 in tumor development.Frontiers in immunology · 2022Review
- Hypoxia Activates Notch4 via ERK/JNK/P38 MAPK Signaling Pathways to Promote Lung Adenocarcinoma Progression and Metastasis.Frontiers in cell and developmental biology · 2021Article
- Xpro®1595 alleviates neuropathic pain by targeting spinal dorsal horn ADAM17-mediated inflammation.Neurobiology of pain (Cambridge, Mass.)Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We previously found the SLC3A2-NRG1 (S-N) fusion gene in a lung adenocarcinoma specimen without known driver mutations and validated this in 59 invasive mucinous adenocarcinoma (IMA) samples. Interestingly, KRAS mutation coexisted (62.5%) in 10 out of 16 NRG1 fusions. In this study, we examined the role of mutant KRAS in regulating the S-N fusion protein in KRAS mutant (H358) and wild-type (Calu-3) cells. KRAS mutation-mediated increase in MEK1/2 and ERK1/2 activity enhanced disintegrin and metalloproteinase (ADAM)17 activity, which increased the shedding of NRG1 from the S-N fusion protein. The cleavage of NRG1 also increased the phosphorylation of ERBB2-ERBB3 heterocomplex receptors and their downstream signalling pathways, including PI3K/Akt/mTOR, even under activated KRAS mutation signalling. The concurrence of S-N fusion and KRAS mutation synergistically increased cell proliferation, colony formation, tumour growth, and the cells' resistance to EGFR kinase inhibitors more than KRAS mutation alone. Targeted inhibition of MEK1/2, and ADAM17 significantly induced apoptosis singly and when combined with each mutation singly or with chemotherapy in both the concurrent KRAS mutant and S-N fusion xenograft and lung orthotopic models. Taken together, this is the first study to report that KRAS mutation increased NRG1 cleavage from the S-N fusion protein through ADAM17, thereby enhancing the Ras/Raf/MEK/ERK and ERBB/PI3K/Akt/mTOR pathways. Moreover, the coexistence of KRAS mutant and S-N fusion in lung tumours renders them vulnerable to MEK1/2 and/or ADAM17 inhibitors, at least in part, due to their dependency on the strong positive loop between KRAS mutation and S-N fusion.
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