ArticleCancer biology & therapy2018
The irreversible ERBB1/2/4 inhibitor neratinib interacts with the PARP1 inhibitor niraparib to kill ovarian cancer cells.
Article in Cancer biology & therapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 33 citations in OpenAlex.
- Review
- Enhancing PARP inhibitor efficacy in ovarian cancer: targeting the PI3K/AKT/mTOR pathway.Journal of ovarian research · 2025Review
- Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers.Gynecologic oncology · 2025Review
- Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy.Cancer biology & medicine · 2023Review
- PARP inhibitors: enhancing efficacy through rational combinations.British journal of cancer · 2023Review
- Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.Cancer research · 2023Article
- Targeting receptor tyrosine kinases in ovarian cancer: Genomic dysregulation, clinical evaluation of inhibitors, and potential for combinatorial therapies.Molecular therapy oncolytics · 2023Review
- The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo.Gynecologic oncology · 2023Article
- Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review).International journal of oncology · 2023Review
- Strategies in Overcoming Homologous Recombination Proficiency and PARP Inhibitor Resistance.Molecular cancer therapeutics · 2021Review
- Article
- 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
- Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors.British journal of cancer · 2021Article
- The role of cell signaling in the crosstalk between autophagy and apoptosis in the regulation of tumor cell survival in response to sorafenib and neratinib.Seminars in cancer biology · 2020Review
- Cathepsin B: A sellsword of cancer progression.Cancer letters · 2019Review
- Prior exposure of pancreatic tumors to [sorafenib + vorinostat] enhances the efficacy of an anti-PD-1 antibody.Cancer biology & therapy · 2019Article
- Human epidermal growth factor receptor targeted inhibitors for the treatment of ovarian cancer.Cancer biology & medicine · 2018Article
- Valproate augments Niraparib killing of tumor cells.Cancer biology & therapy · 2018Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ovarian cancer cells. Neratinib and niraparib caused the ATM-dependent activation of AMPK which in turn was required to cause mTOR inactivation, ULK-1 activation and ATG13 phosphorylation. The drug combination initially increased autophagosome levels followed later by autolysosome levels. Preventing autophagosome formation by expressing activated mTOR or knocking down of Beclin1, or knock down of the autolysosome protein cathepsin B, reduced drug combination lethality. The drug combination caused an endoplasmic reticulum stress response as judged by enhanced eIF2α phosphorylation that was responsible for reducing MCL-1 and BCL-XL levels and increasing ATG5 and Beclin1 expression. Knock down of BIM, but not of BAX or BAK, reduced cell killing. Expression of activated MEK1 prevented the drug combination increasing BIM expression and reduced cell killing. Downstream of the mitochondrion, drug lethality was partially reduced by knock down of AIF, but expression of dominant negative caspase 9 was not protective. Our data demonstrate that neratinib and niraparib interact to kill ovarian cancer cells through convergent DNA damage and endoplasmic reticulum stress signaling. Cell killing required the induction of autophagy and was cathepsin B and AIF -dependent, and effector caspase independent.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.