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

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

  • Sci Signal. 2025 Feb 11;18(873):eado2857. doi: 10.1126/scisignal.ado2857.
Amy L Funk 1,  Meghri Katerji 1,  Marwa Afifi 2,  Katherine Nyswaner 1,  Carolyn C Woodroofe 3,  Zoe C Edwards 4,  Eric Lindberg 3,  Knickole L Bergman 1,  Nancy R Gough 5,  Maxine R Rubin 1,  Kamila Karpińska 6,  Eleanor W Trotter 4,  Sweta Dash 1,  Amy L Ries 7,  Amy James 7,  Christina M Robinson 7,  Simone Difilippantonio 7,  Baktiar O Karim 8,  Ting-Chia Chang 9,  Li Chen 9,  Xin Xu 10,  James H Doroshow 10,  Ivan Ahel 11,  Anna A Marusiak 6,  Rolf E Swenson 3,  Steven D Cappell 2,  John Brognard 1
Affiliations

Affiliations

  • 1 Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD 21702, USA.
  • 2 Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
  • 3 Chemistry and Synthesis Center, National Heart, Lung, and Blood Institute, NIH, Rockville, MD 20850, USA.
  • 4 Cell Division Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
  • 5 BioSerendipity, LLC, Elkridge, MD 21075, USA.
  • 6 Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Warsaw, Poland.
  • 7 Laboratory Animal Sciences Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 8 Molecular Histopathology Laboratory, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 9 Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
  • 10 Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Rockville, MD 20850, USA.
  • 11 Sir William Dunn School of Pathology, Oxford OX1 3RE, UK.
PMID: 39933019 DOI: 10.1126/scisignal.ado2857
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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