ArticleAmerican journal of cancer research2016
Afatinib down-regulates MCL-1 expression through the PERK-eIF2α-ATF4 axis and leads to apoptosis in head and neck squamous cell carcinoma.
Article in American journal of cancer research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 25 citations in OpenAlex.
- Evaluating the Therapeutic Potential of MRT68921 and Afatinib in Three-Dimensional Models of Epithelial Ovarian Cancer.Cancers · 2026Article
- MYH9 confers doxorubicin resistance by stabilizing GRP78 and suppressing the PERK signaling-driven apoptotic pathway in breast cancer.Frontiers in oncology · 2026Article
- ONC201 enhances the cytotoxic effect of cisplatin through ATF3/ATF4/CHOP in head and neck squamous cell carcinoma cells.Oncogenesis · 2025Article
- PUMA mediated afatinib-induced apoptosis in glioma cells.Archives of medical science : AMS · 2025Article
- Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes.BMC medicine · 2023Article
- Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma.Biomarker research · 2023Review
- Myeloid cell leukemia-1 expression in cancers of the oral cavity: a scoping review.Cancer cell international · 2022Article
- Afatinib induces pro-survival autophagy and increases sensitivity to apoptosis in stem-like HNSCC cells.Cell death & disease · 2021Article
- Apoptosis signaling molecules as treatment targets in head and neck squamous cell carcinoma.The Laryngoscope · 2020Article
- Targeting the unfolded protein response in head and neck and oral cavity cancers.Experimental cell research · 2019Review
- (3Experimental and therapeutic medicine · 2019Article
- Impact and Relevance of the Unfolded Protein Response in HNSCC.International journal of molecular sciences · 2019Review
- Targeting KPNB1 overcomes TRAIL resistance by regulating DR5, Mcl-1 and FLIP in glioblastoma cells.Cell death & disease · 2019Article
- Pemetrexed exerts anticancer effects by inducing GOncology letters · 2019Article
- Optimal targeting of BCL-family proteins in head and neck squamous cell carcinoma requires inhibition of both BCL-xL and MCL-1.Oncotarget · 2019Article
- Interferon γ suppresses dentin sialophosphoprotein in oral squamous cell carcinoma cells resulting in antitumor effects, via modulation of the endoplasmic reticulum response.International journal of oncology · 2018Article
- Simultaneous targeting of EGFR, HER2, and HER4 by afatinib overcomes intrinsic and acquired cetuximab resistance in head and neck squamous cell carcinoma cell lines.Molecular oncology · 2018Article
- Appropriate Sequence for Afatinib and Cisplatin Combination Improves Anticancer Activity in Head and Neck Squamous Cell Carcinoma.Frontiers in oncology · 2018Article
- Modulation of Navitoclax Sensitivity by Dihydroartemisinin-Mediated MCL-1 Repression in BCR-ABLClinical cancer research : an official journal of the American Association for Cancer Research · 2017Article
- Structure Identification and In Vitro Anticancer Activity of Lathyrol-3-phenylacetate-5,15-diacetate.Molecules (Basel, Switzerland) · 2017Article
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Afatinib is the second generation of irreversible inhibitor of EGFR, HER2 and HER4, which has shown encouraging phase II and III clinical outcomes in the treatment of head and neck squamous cell carcinoma (HNSCC). However, the molecular mechanism of afatinib-induced apoptosis in HNSCC is poorly understood. In the present investigation, we discovered that down-regulation of MCL-1, an anti-apoptotic member of BCL-2 family, was responsible for afatinib-triggered apoptosis. And the inactivation of AKT-mTOR signaling caused by afatinib lead to translational inhibition of MCL-1 expression. As a crucial branch of ER stress, PERK-eIF2α-ATF4 axis was also stimulated in HNSCC cells after afatinib incubation. Silencing either eIF2α or ATF4 by siRNA transfection relieved afatinib-caused suppression of AKT-mTOR activity, attenuating MCL-1 down-regulation as well as subsequent apoptosis. Collectively, the results show that afatinib hampers AKT-mTOR activation by stimulating PERK-eIF2α-ATF4 signaling pathway, giving rise to MCL-1 down-regulation mediated apoptosis in HNSCC cells. Therefore, our findings reveal the elaborate molecular network of afatinib-induced apoptosis in HNSCC, which would provide substantial theoretical underpinnings for afatinib clinical application and highlight its promising prospect in HNSCC treatment.
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Identifiers
27648360PMC5004074W2534121211What OpenQuestion holds
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.