biostudies-literatureUnknownFunk ALIntramural NIH HHSNCI NIH HHSThe 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 <i>MAP3K13</i>) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified <i>MAP3K13</i>. 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 <i>MAP3K13</i>. 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-tbioRxiv : the preprint server for biology2024.11.19.623840https://www.ebi.ac.uk/biostudies/studies/S-EPMC11601640biostudies-literatureTargeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth.PMC11601640ZIA BC011691HHSN261201500003IHHSN261201500003CKarpinska KChang TCSwenson REAhel IFunk ALJames ARies ALMarusiak AACappell SDAfifi MRubin MRDifilippantonio SKaterji MEdwards ZCBergman KLGough NRRobinson CMChen LTrotter EWDash SDoroshow JHWoodroofe CCBrognard JKarim BOXu XNyswaner KLindberg EfalseTargeting GOF p53 and c-MYC through LZK Inhibition or Degradation Suppresses Head and Neck Tumor Growth.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 <i>MAP3K13</i>) is a therapeutic target in HNSCC and showed that inhibition with small molecule inhibitors decreases the viability of HNSCC cells with amplified <i>MAP3K13</i>. 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 <i>MAP3K13</i>. 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-t2024-01-01T00:00:00Z2024 Nov2025-04-04T12:01:20.17Z2025-04-04T12:01:20.17ZS-EPMC116016403960556310.1101/2024.11.19.623840