PMID- 33495197 OWN - NLM STAT- MEDLINE DCOM- 20220218 LR - 20221005 IS - 2159-8290 (Electronic) IS - 2159-8274 (Print) IS - 2159-8274 (Linking) VI - 11 IP - 6 DP - 2021 Jun TI - TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin. PG - 1411-1423 LID - 10.1158/2159-8290.CD-20-0797 [doi] AB - 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 pharmacologic 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. SIGNIFICANCE: Targeted therapies have not yet been approved for the treatment of LSCC, due to lack of identification of actionable cancer drivers. We define TNIK catalytic activity as essential for maintaining LSCC viability and validate the antitumor efficacy of TNIK inhibition in preclinical models of LSCC.This article is highlighted in the In This Issue feature, p. 1307. CI - (c)2021 American Association for Cancer Research. FAU - Torres-Ayuso, Pedro AU - Torres-Ayuso P AUID- ORCID: 0000-0003-2213-9014 AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. john.brognard@nih.gov torresayusop2@nih.gov. FAU - An, Elvira AU - An E AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Nyswaner, Katherine M AU - Nyswaner KM AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Bensen, Ryan C AU - Bensen RC AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Ritt, Daniel A AU - Ritt DA AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Specht, Suzanne I AU - Specht SI AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Das, Sudipto AU - Das S AD - Protein Characterization Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Andresson, Thorkell AU - Andresson T AD - Protein Characterization Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Cachau, Raul E AU - Cachau RE AD - Advanced Biomedical Computational Science, Biomedical Informatics and Data Science, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Liang, Roger J AU - Liang RJ AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Ries, Amy L AU - Ries AL AD - Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Robinson, Christina M AU - Robinson CM AD - Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Difilippantonio, Simone AU - Difilippantonio S AD - Laboratory Animal Sciences Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Gouker, Brad AU - Gouker B AD - Molecular Histopathology Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Bassel, Laura AU - Bassel L AD - Molecular Histopathology Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Karim, Baktiar O AU - Karim BO AD - Molecular Histopathology Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland. FAU - Miller, Chad J AU - Miller CJ AUID- ORCID: 0000-0002-2087-6566 AD - Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut. FAU - Turk, Benjamin E AU - Turk BE AUID- ORCID: 0000-0001-9275-4069 AD - Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut. FAU - Morrison, Deborah K AU - Morrison DK AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. FAU - Brognard, John AU - Brognard J AD - Laboratory of Cell and Developmental Signaling, Center for Cancer Research, NCI, Frederick, Maryland. john.brognard@nih.gov torresayusop2@nih.gov. LA - eng GR - 75N91019D00024/CA/NCI NIH HHS/United States GR - R01 GM102262/GM/NIGMS NIH HHS/United States GR - ZIA BC011691/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20210125 PL - United States TA - Cancer Discov JT - Cancer discovery JID - 101561693 RN - 0 (Antineoplastic Agents) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (TNIK protein, human) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Carcinoma, Squamous Cell/*drug therapy/genetics MH - Cell Line, Tumor/drug effects MH - Epithelial Cells/drug effects MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/*drug therapy/genetics MH - Mice MH - Molecular Targeted Therapy MH - Protein Kinase Inhibitors/pharmacology/*therapeutic use MH - Protein Serine-Threonine Kinases/*antagonists & inhibitors/genetics PMC - PMC8178189 MID - NIHMS1668020 COIS- Conflict of interest: The authors declare no potential conflicts of interest. EDAT- 2021/01/27 06:00 MHDA- 2022/02/19 06:00 PMCR- 2021/12/01 CRDT- 2021/01/26 05:37 PHST- 2020/06/05 00:00 [received] PHST- 2020/11/21 00:00 [revised] PHST- 2021/01/20 00:00 [accepted] PHST- 2021/01/27 06:00 [pubmed] PHST- 2022/02/19 06:00 [medline] PHST- 2021/01/26 05:37 [entrez] PHST- 2021/12/01 00:00 [pmc-release] AID - 2159-8290.CD-20-0797 [pii] AID - 10.1158/2159-8290.CD-20-0797 [doi] PST - ppublish SO - Cancer Discov. 2021 Jun;11(6):1411-1423. doi: 10.1158/2159-8290.CD-20-0797. Epub 2021 Jan 25.