ArticleOncogene2019
Neratinib inhibits Hippo/YAP signaling, reduces mutant K-RAS expression, and kills pancreatic and blood cancer cells.
Article in Oncogene, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 85 citations in OpenAlex.
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- Inhibition of the RAF/MEK/ERK Signaling Cascade in Pancreatic Cancer: Recent Advances and Future Perspectives.International journal of molecular sciences · 2024Review
- Neratinib for HER2-positive breast cancer with an overlooked option.Molecular medicine (Cambridge, Mass.) · 2023Review
- Dishevelled 2 regulates cancer cell proliferation and T cell mediated immunity in HER2-positive breast cancer.BMC cancer · 2023Article
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- Drug Repurposing against KRAS Mutant G12C: A Machine Learning, Molecular Docking, and Molecular Dynamics Study.International journal of molecular sciences · 2022Article
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- Emerging kinase inhibitors for the treatment of pancreatic ductal adenocarcinoma.Expert opinion on emerging drugs · 2022Review
- RNF6 promotes the migration and invasion of breast cancer by promoting the ubiquitination and degradation of MST1.Experimental and therapeutic medicine · 2022Article
- IPO7 promotes pancreatic cancer progression via regulating ERBB pathway.Clinics (Sao Paulo, Brazil) · 2022Article
- Case Report: Neratinib Therapy Improves Glycemic Control in a Patient With Type 2 Diabetes and Breast Cancer.Frontiers in endocrinology · 2022Article
- Neratinib kills B-RAF V600E melanoma via ROS-dependent autophagosome formation and death receptor signaling.Pigment cell & melanoma research · 2022Article
- E3 ubiquitin ligase TRIM29 promotes pancreatic cancer growth and progression via stabilizing Yes-associated protein 1.Journal of translational medicine · 2021Article
- Osimertinib-resistant NSCLC cells activate ERBB2 and YAP/TAZ and are killed by neratinib.Biochemical pharmacology · 2021Article
- Artesunate combined with verteporfin inhibits uveal melanoma by regulation of theOncology letters · 2021Article
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- Imaging of Endocytic Trafficking and Extracellular Vesicles Released Under Neratinib Treatment in ERBB2The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society · 2021Article
- SEPT6 drives hepatocellular carcinoma cell proliferation, migration and invasion via the Hippo/YAP signaling pathway.International journal of oncology · 2021Observational
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 1 country.
Funding
Abstract
Prior studies demonstrated that the irreversible ERBB1/2/4 inhibitor neratinib caused plasma membrane-associated mutant K-RAS to localize in intracellular vesicles, concomitant with its degradation. Herein, we discovered that neratinib interacted with the chemically distinct irreversible ERBB1/2/4 inhibitor afatinib to reduce expression of ERBB1, ERBB2, K-RAS and N-RAS; this was associated with greater-than-additive cell killing of pancreatic tumor cells. Knock down of Beclin1, ATG16L1, Rubicon or cathepsin B significantly lowered the ability of neratinib to reduce ERBB1 and K-RAS expression, and to cause tumor cell death. Knock down of ATM-AMPK suppressed vesicle formation and knock down of cathepsin B-AIF significantly reduced neratinib lethality. PKG phosphorylates K-RAS and HMG CoA reductase inhibitors reduce K-RAS farnesylation both of which remove K-RAS from the plasma membrane, abolishing its activity. Neratinib interacted with the PKG activator sildenafil and the HMG CoA reductase inhibitor atorvastatin to further reduce K-RAS expression, and to further enhance cell killing. Neratinib is also a Ste20 kinase family inhibitor and in carcinoma cells, and hematopoietic cancer cells lacking ERBB1/2/4, it reduced K-RAS expression and the phosphorylation of MST1/3/4/Ezrin by ~ 30%. Neratinib increased LATS1 phosphorylation as well as that of YAP and TAZ also by ~ 30%, caused the majority of YAP to translocate into the cytosol and reduced YAP/TAZ protein levels. Neratinib lethality was enhanced by knock down of YAP. Neratinib, in a Rubicon-dependent fashion, reduced PAK1 phosphorylation and that of its substrate Merlin. Our data demonstrate that neratinib coordinately suppresses both mutant K-RAS and YAP function to kill pancreatic tumor cells.
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