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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Head and neck squamous cell carcinoma (HNSCC) presents a significant global health challenge with high incidence and mortality.
• Amplification of the MAP3K13 gene, encoding LZK, is observed in HNSCC, suggesting its potential as a therapeutic target.

Purpose of the Study:

• To investigate LZK as a therapeutic target in HNSCC.
• To evaluate the efficacy of small molecule inhibitors and proteolysis-targeting chimeras (PROTACs) targeting LZK in HNSCC models.

Main Methods:

• Utilized small molecule inhibitors targeting LZK catalytic activity in HNSCC cell lines and patient-derived xenograft (PDX) models.
• Investigated LZK's role in stabilizing c-MYC and gain-of-function p53.
• Designed and tested PROTACs to induce LZK degradation.

Main Results:

• Small molecule inhibition of LZK reduced HNSCC cell viability, particularly in cells with MAP3K13 amplification.
• LZK kinase activity stabilized c-MYC, while a kinase-independent mechanism stabilized gain-of-function p53.
• The lead PROTAC effectively degraded LZK, suppressed GOF p53 and c-MYC, and impaired HNSCC cell viability.

Conclusions:

• LZK is a validated therapeutic target in HNSCC, especially in tumors with MAP3K13 amplification.
• Targeting LZK through direct inhibition or PROTAC-mediated degradation offers a promising therapeutic strategy for HNSCC.