Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin

Pedro Torres-Ayuso; Elvira An; Katherine M. Nyswaner; Ryan C. Bensen; Daniel A. Ritt; Suzanne I. Specht; Sudipto Das; Thorkell Andresson; Raul E. Cachau; Roger J. Liang; Amy L. Ries; Christina M. Robinson; Simone Difilippantonio; Brad Gouker; Laura Bassel; Baktiar O. Karim; Chad J. Miller; Benjamin E. Turk; Deborah K. Morrison; John Brognard

doi:10.1158/2159-8290.CD-20-0797

Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin

Pedro Torres-Ayuso, Elvira An, Katherine M. Nyswaner, Ryan C. Bensen, Daniel A. Ritt, Suzanne I. Specht, Sudipto Das, Thorkell Andresson, Raul E. Cachau, Roger J. Liang, Amy L. Ries, Christina M. Robinson, Simone Difilippantonio, Brad Gouker, Laura Bassel, Baktiar O. Karim, Chad J. Miller, Benjamin E. Turk, Deborah K. Morrison, John Brognard

Cancer Signaling and Microenvironment (CSM)

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1411-1423
Number of pages	13
Journal	Cancer Discovery
Volume	11
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-20-0797
State	Published - Jun 1 2021

Keywords

Animals
Antineoplastic Agents/pharmacology
Carcinoma, Squamous Cell/drug therapy
Cell Line, Tumor/drug effects
Epithelial Cells/drug effects
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms/drug therapy
Mice
Molecular Targeted Therapy
Protein Kinase Inhibitors/pharmacology
Protein Serine-Threonine Kinases/antagonists & inhibitors

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10.1158/2159-8290.CD-20-0797

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Torres-Ayuso, P., An, E., Nyswaner, K. M., Bensen, R. C., Ritt, D. A., Specht, S. I., Das, S., Andresson, T., Cachau, R. E., Liang, R. J., Ries, A. L., Robinson, C. M., Difilippantonio, S., Gouker, B., Bassel, L., Karim, B. O., Miller, C. J., Turk, B. E., Morrison, D. K., & Brognard, J. (2021). Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin. Cancer Discovery, 11(6), 1411-1423. https://doi.org/10.1158/2159-8290.CD-20-0797

@article{05dd7dc3b1b947a8ae88c68ea9bc4d61,

title = "Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin",

abstract = "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.",

keywords = "Animals, Antineoplastic Agents/pharmacology, Carcinoma, Squamous Cell/drug therapy, Cell Line, Tumor/drug effects, Epithelial Cells/drug effects, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms/drug therapy, Mice, Molecular Targeted Therapy, Protein Kinase Inhibitors/pharmacology, Protein Serine-Threonine Kinases/antagonists & inhibitors",

author = "Pedro Torres-Ayuso and Elvira An and Nyswaner, {Katherine M.} and Bensen, {Ryan C.} and Ritt, {Daniel A.} and Specht, {Suzanne I.} and Sudipto Das and Thorkell Andresson and Cachau, {Raul E.} and Liang, {Roger J.} and Ries, {Amy L.} and Robinson, {Christina M.} and Simone Difilippantonio and Brad Gouker and Laura Bassel and Karim, {Baktiar O.} and Miller, {Chad J.} and Turk, {Benjamin E.} and Morrison, {Deborah K.} and John Brognard",

note = "Publisher Copyright: {\textcopyright}2021 American Association for Cancer Research.",

year = "2021",

month = jun,

day = "1",

doi = "10.1158/2159-8290.CD-20-0797",

language = "English",

volume = "11",

pages = "1411--1423",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "6",

}

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 2021, 'Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin', Cancer Discovery, vol. 11, no. 6, pp. 1411-1423. https://doi.org/10.1158/2159-8290.CD-20-0797

TY - JOUR

T1 - Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin

AU - Torres-Ayuso, Pedro

AU - An, Elvira

AU - Nyswaner, Katherine M.

AU - Bensen, Ryan C.

AU - Ritt, Daniel A.

AU - Specht, Suzanne I.

AU - Das, Sudipto

AU - Andresson, Thorkell

AU - Cachau, Raul E.

AU - Liang, Roger J.

AU - Ries, Amy L.

AU - Robinson, Christina M.

AU - Difilippantonio, Simone

AU - Gouker, Brad

AU - Bassel, Laura

AU - Karim, Baktiar O.

AU - Miller, Chad J.

AU - Turk, Benjamin E.

AU - Morrison, Deborah K.

AU - Brognard, John

PY - 2021/6/1

Y1 - 2021/6/1

N2 - 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.

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.

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Carcinoma, Squamous Cell/drug therapy

KW - Cell Line, Tumor/drug effects

KW - Epithelial Cells/drug effects

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Mice

KW - Molecular Targeted Therapy

KW - Protein Kinase Inhibitors/pharmacology

KW - Protein Serine-Threonine Kinases/antagonists & inhibitors

UR - https://doi.org/10.1158/2159-8290.CD-20-0797

U2 - 10.1158/2159-8290.CD-20-0797

DO - 10.1158/2159-8290.CD-20-0797

M3 - Article

C2 - 33495197

SN - 2159-8274

VL - 11

SP - 1411

EP - 1423

JO - Cancer Discovery

JF - Cancer Discovery

IS - 6

ER -

Tnik is a therapeutic target in lung squamous cell carcinoma and regulates fak activation through merlin

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