ArticleOncology signaling2018
NEDD4 over-expression regulates the afatinib resistant phenotype of NSCLC cells.
Article in Oncology signaling, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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The trial behind it
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
6 citing papers in PubMed, 10 citations in OpenAlex.
- The E3 ubiquitin ligase NEDD4 regulates chemoresistance to 5-fluorouracil in colorectal cancer cells by altering JNK signalling.Cell death & disease · 2023Article
- Osimertinib-resistant NSCLC cells activate ERBB2 and YAP/TAZ and are killed by neratinib.Biochemical pharmacology · 2021Article
- Identification and Validation of an Immune and Ferroptosis-Combined Index for Non-Small Cell Lung Cancer.Frontiers in genetics · 2021Article
- Fingolimod augments Pemetrexed killing of non-small cell lung cancer and overcomes resistance to ERBB inhibition.Cancer biology & therapy · 2019Article
- Kinase inhibitors: look beyond the label on the bottle.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- HDAC inhibitors enhance neratinib activity and when combined enhance the actions of an anti-PD-1 immunomodulatory antibodyOncotarget · 2017Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
We focused on defining the role of the E3 ligase NEDD4 in NSCLC cell afatinib resistance. Afatinib resistant H1975 clones over-expressed NEDD4 and c-MET compared to control clones and expressed less ERBB1, ERBB3, ERBB4 and PTEN than control clones. Knock down of NEDD4 enhanced the expression of PTEN, ERBB1/3/4 and c-MET. This was also associated with a ∼3-fold enhancement in both mTOR expression and mTOR phosphorylation and a ∼4-fold elevation in phospho-ULK-1 S757 levels. In the absence of NEDD4 or the autophagy regulatory protein Beclin1, neither the drug combination of [pemetrexed + sildenafil] nor the HDAC inhibitor sodium valproate was as capable of: reducing the expression of ERBB1/3/4; reducing phosphorylation of ULK-1 S757; or at enhancing the phosphorylation of ULK-1 S317 and ATG13 S318. [Pemetrexed + sildenafil] exposure, via autophagic degradation, reduced the expression of multiple HDACs. Reduced expression of Class I HDACs lowered the expression of ERBB1/3/4 and PTEN. Treatment of afatinib resistant clones lacking NEDD4 with [pemetrexed + sildenafil] or sodium valproate resulted in a weaker induction of autophagosome and autolysosome formation and with reduced cell killing. Knock down of NEDD4 reduced [pemetrexed + sildenafil] lethality; knock down of PTEN enhanced drug-induced killing. Combined knock down of NEDD4 and PTEN reduced the elevated amount of killing caused by PTEN knock down alone back to basal levels. Collectively, our data argue that NEDD4 plays an essential role in maintaining the afatinib-resistant phenotype in our resistant H1975 clones.
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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.