Funk Amy L, Katerji Meghri, Afifi Marwa, Nyswaner Katherine, Woodroofe Carolyn C, Edwards Zoe C, Lindberg Eric, Bergman Knickole L, Gough Nancy R, Rubin Maxine R, Karpińska Kamila, Trotter Eleanor W, Dash Sweta, Ries Amy L, James Amy, Robinson Christina M, Difilippantonio Simone, Karim Baktiar O, Chang Ting-Chia, Chen Li, Xu Xin, Doroshow James H, Ahel Ivan, Marusiak Anna A, Swenson Rolf E, Cappell Steven D, Brognard John
Laboratory of Cell and Developmental Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, MD 21702, USA.
Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892-4255, USA.
Sci Signal. 2025 Feb 11;18(873):eado2857. doi: 10.1126/scisignal.ado2857.
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 , 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 . Inhibition of LZK suppressed tumor growth in -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 amplification.
头颈部鳞状细胞癌（HNSCC）的全球年度发病率和致死率并未改善，因此需要新的治疗方法。大约70%的HNSCC病例存在编码激酶LZK的基因的扩增或过表达。在此，我们发现LZK是HNSCC的一个治疗靶点，对其催化功能的小分子抑制降低了具有该基因扩增的HNSCC细胞的活力。抑制LZK可抑制源自HNSCC患者的该基因扩增的异种移植瘤的生长。LZK通过其激酶活性稳定转录因子c-MYC，并以激酶非依赖的方式稳定p53的功能获得性突变体。我们设计了一种靶向蛋白水解嵌合体（PROTAC），其可诱导LZK降解，导致c-MYC和功能获得性p53的丰度降低，并降低HNSCC细胞的活力。我们的研究结果表明，靶向LZK的疗法，尤其是PROTAC，可能对治疗具有该基因扩增的HNSCC有效。
