Targeting c-MYC and gain-of-function p53 through inhibition or degradation of the kinase LZK suppresses the growth of HNSCC tumors

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2025-02-11

Amy L. Funk, Meghri Katerji, Marwa Afifi, Katherine Nyswaner, Carolyn C. Woodroofe, Zoe C. Edwards, Eric Lindberg, Knickole L. Bergman, Nancy R. Gough, Maxine R. Rubin, Kamila Karpińska, Eleanor W. Trotter, Sweta Dash, Amy L. Ries, Amy James, Christina M. Robinson, Simone Difilippantonio, Baktiar O. Karim, Ting-Chia Chang, Li Chen, Xin Xu, James H. Doroshow, Ivan Ahel, Anna A. Marusiak, Rolf E. Swenson, Steven D. Cappell, John Brognard

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Abstract

The worldwide annual frequency and lethality of head and neck squamous cell carcinoma (HNSCC) is not improving, and thus, new therapeutic approaches are needed. Approximately 70% of HNSCC cases have either amplification or overexpression of MAP3K13, which encodes the kinase LZK. Here, we found that LZK is a therapeutic target in HNSCC and that small-molecule inhibition of its catalytic function decreased the viability of HNSCC cells with amplified MAP3K13. Inhibition of LZK suppressed tumor growth in MAP3K13-amplified xenografts derived from HNSCC patients. LZK stabilized the transcription factor c-MYC through its kinase activity and gain-of-function mutants of p53 in a kinase-independent manner. We designed a proteolysis-targeting chimera (PROTAC) that induced LZK degradation, leading to decreased abundance of both c-MYC and gain-of-function p53, and reduced the viability of HNSCC cells. Our findings demonstrate that LZK-targeted therapeutics, particularly PROTACs, may be effective in treating HNSCCs with MAP3K13 amplification.

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.