TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.
TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin.
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DOI：
10.1158/2159-8290.cd-20-0797
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发表时间：
2021-06
期刊：
影响因子：
28.2
通讯作者：
Brognard J
中科院分区：
文献类型：
--
作者：
Torres-Ayuso P;An E;Nyswaner KM;Bensen RC;Ritt DA;Specht SI;Das S;Andresson T;Cachau RE;Liang RJ;Ries AL;Robinson CM;Difilippantonio S;Gouker B;Bassel L;Karim BO;Miller CJ;Turk BE;Morrison DK;Brognard J
肺鳞状细胞癌（LSCC）是第二种最常见的肺癌类型。尽管广泛的基因组特征，没有靶向治疗被批准用于治疗喉鳞状细胞癌。3q染色体的远端扩增是喉鳞状细胞癌中最常见的基因组改变，并且迫切需要在该扩增子内鉴定有效的药物靶点。我们确定蛋白激酶TNIK作为喉鳞状细胞癌的治疗靶点。TNIK在大约50%的LSCC病例中扩增。TNIK基因耗竭或药物抑制可降低体外和体内LSCC细胞的生长。此外，TNIK抑制显示出抗肿瘤活性，并在已建立的LSCC患者来源的异种移植物中增加细胞凋亡。从机制上讲，我们确定了肿瘤抑制因子Merlin/NF 2作为一种新的TNIK底物，并表明TNIK和Merlin是激活粘着斑激酶所必需的。总之，我们的数据确定靶向TNIK作为一个潜在的治疗策略在喉鳞状细胞癌。
Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon. We identify the protein kinase TNIK as a therapeutic target in LSCC. TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacological inhibition reduces the growth of LSCC cells in vitro and in vivo. In addition, TNIK inhibition showed antitumor activity and increased apoptosis in established LSCC patient-derived xenografts. Mechanistically, we identified the tumor suppressor Merlin/NF2 as a novel TNIK substrate and showed that TNIK and Merlin are required for the activation of focal adhesion kinase. In conclusion, our data identify targeting TNIK as a potential therapeutic strategy in LSCC.