Title |
Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers
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Published in |
Molecular Cancer Research, February 2022
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DOI | 10.1158/1541-7786.mcr-21-0624 |
Pubmed ID | |
Authors |
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 L. Morgan |
Abstract |
Tumor Necrosis Factor-a (TNFa) is a key mediator of immune and radiation-induced cytotoxicity, but many cancers, including head and neck squamous cell carcinomas (HNSCC), display TNF resistance due to activation of the canonical IKK-NF-κB/RELA pro-survival pathway. However, toxicities associated with direct targeting of the canonical pathway point to the need to identify mechanism(s) contributing to TNFα resistance and synthetic lethal targets to overcome such resistance in cancer cells. Here, RNAi screening for modulators of TNFα-NF-κB reporter activity and cell survival unexpectedly implicated the WEE1 and CDC2 G2/M checkpoint kinases. The IKKα/β-RELA and WEE1-CDC2 signaling pathways are activated by TNFα and form a complex in cell lines derived from both Human Papilloma Virus (-) and (+) subtypes of HNSCC. WEE1 inhibitor AZD1775 reduced IKK/RELA phosphorylation and the expression of NF-κB-dependent pro-survival proteins Cyclin D1 and BCL2. Combination of TNFα and AZD1775 enhanced caspase-mediated apoptosis in vitro, and combination treatment with radiation and AZD1775 potentiated inhibition of HNSCC tumor xenograft growth in vivo, which could be significantly attenuated by TNFα depletion. These data offer new insight into the interplay between NF-κB 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 TNFα with less systemic immune suppression and toxicity than observed with direct interruption of IKK-NF-κB/RELA signaling. |
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Researcher | 2 | 29% |
Unspecified | 1 | 14% |
Professor > Associate Professor | 1 | 14% |
Student > Master | 1 | 14% |
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