2. Academic Validation
  3. Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth

Targeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth

  • bioRxiv. 2024 Nov 20:2024.11.19.623840. doi: 10.1101/2024.11.19.623840.
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 1,  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, National Institutes of Health, Rockville, MD 20850, USA.
  • 4 Cell Division Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
  • 5 BioSerendipity, LLC, Frederick, MD 21702, 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 UK, OX1 3RE.
PMID: 39605563 DOI: 10.1101/2024.11.19.623840
Abstract

The worldwide frequency of head and neck squamous cell carcinoma (HNSCC) is approximately 800,000 new cases, with 430,000 deaths annually. We determined that LZK (encoded by MAP3K13) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified MAP3K13. A drug-resistant mutant of LZK blocks decreases in cell viability due to LZK inhibition, indicating on-target activity by two separate small molecules. Inhibition of LZK catalytic activity suppressed tumor growth in HNSCC PDX models with amplified MAP3K13. We found that the kinase activity of LZK stabilized c-Myc and that LZK stabilized gain-of-function (GOF) p53 through a kinase-independent mechanism. Therefore, we designed proteolysis-targeting chimeras (PROTACs) and demonstrate that our lead PROTAC promotes LZK degradation and suppresses expression of GOF p53 and c-Myc leading to impaired viability of HNSCC cell lines. This research provides a strong basis for development of therapeutics targeting LZK in HNSCCs with amplification of the gene.

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