Inhibiting%20WEE1%20and%20IKK-RELA%20Crosstalk%20Overcomes%20TNF%CE%B1%20Resistance%20in%20Head%20and%20Neck%20Cancers%5B60%5D.pdf (3.32 MB)
Inhibiting WEE1 and IKK-RELA crosstalk overcomes TNFa resistance in head and neck cancers
journal contribution
posted on 2023-06-15, 15:41 authored by Zhengbo Hu, Ramya Viswanathan, Hui Cheng, Jianghong Chen, Xinping Yang, Angel Huynh, Paul Clavijo, Yi An, Yvette Robbins, Christopher Silvin, Clint Allen, Pinar Ormanoglu, Scott Martin, Shaleeka Cornelius, Anthony Saleh, Zhong Chen, Carter Van Waes, Ethan MorganEthan MorganTNFa is a key mediator of immune and radiotherapy-induced cytotoxicity, but many cancers, including head and neck squamous cell carcinomas (HNSCC), display TNF resistance due to activation of the canonical IKK–NF-?B/RELA pro-survival pathway. However, toxicities associated with direct targeting of the canonical pathway point to the need to identify mechanism(s) contributing to TNFa resistance and synthetic lethal targets to overcome such resistance in cancer cells. Here, RNAi screening for modulators of TNFa–NF-?B reporter activity and cell survival unexpectedly implicated the WEE1 and CDC2 G2–M checkpoint kinases. The IKKa/ß-RELA and WEE1-CDC2 signaling pathways are activated by TNFa and form a complex in cell lines derived from both human papillomavirus (-) and (+) subtypes of HNSCC. WEE1 inhibitor AZD1775 reduced IKK/RELA phosphorylation and the expression of NF-?B–dependent pro-survival proteins Cyclin D1 and BCL2. Combination of TNFa and AZD1775 enhanced caspase-mediated apoptosis in vitro, and combination treatment with radiotherapy and AZD1775 potentiated inhibition of HNSCC tumor xenograft growth in vivo, which could be significantly attenuated by TNFa depletion. These data offer new insight into the interplay between NF-?B signaling and WEE1-mediated regulation of the G2–M cell-cycle checkpoint in HNSCC. Implications Inhibiting WEE1 and IKK-RELA crosstalk could potentially enhance the effects of therapies mediated by TNFa with less systemic immune suppression and toxicity than observed with direct interruption of IKK-NF-?B/RELA signaling.
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Publication status
- Published
File Version
- Accepted version
Journal
Molecular Cancer ResearchISSN
1541-7786Publisher
American Association for Cancer ResearchExternal DOI
Issue
6Volume
20Page range
867-882Event location
United StatesDepartment affiliated with
- Biochemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2023-01-13First Open Access (FOA) Date
2023-02-18First Compliant Deposit (FCD) Date
2023-01-13Usage metrics
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