New Hope for Head and Neck Cancer: Targeting LZK Disrupts Oncogenic c-MYC and Mutant p53 in HNSCC
Editor’s Summary
Many cancers of the head and neck, referred to as HNSCCs, are driven by the undruggable transcription factors c-MYC or mutant p53. Funk et al. found that these oncogenes can be disrupted in HNSCCs by targeting the kinase LZK, another commonly overexpressed protein encoded by MAP3K13. LZK stabilized c-MYC through kinase-dependent activity, whereas LZK stabilized mutant p53 through a kinase-independent physical interaction. A PROTAC drug that degraded LZK resulted in the destabilization of both proteins, and a catalytic inhibitor of LZK slowed the growth of MAP3K13-amplified HNSCCs in mice, highlighting LZK as a target for treating HNSCC.
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.
About the Cancer Cell Signaling & Therapeutics Lab
The Cancer Cell Signaling and Therapeutic Lab’s mission is to uncover the molecular drivers of cancers with limited treatment options and translate these discoveries into targeted therapies. By identifying new vulnerabilities in tumor biology, we aim to develop more precise treatments that improve survival while minimizing toxicity. Ultimately, our goal is to deliver therapies that extend and improve the lives of patients facing the greatest unmet needs.
