DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall surviva...

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Published in:	The Journal of experimental medicine Vol. 219; no. 12
Main Authors:	Valencia, Karmele, Echepare, Mirari, Teijeira, Álvaro, Pasquier, Andrea, Bértolo, Cristina, Sainz, Cristina, Tamayo, Ibon, Picabea, Beñat, Bosco, Graziella, Thomas, Roman, Agorreta, Jackeline, López-Picazo, José María, Frigola, Joan, Amat, Ramon, Calvo, Alfonso, Felip, Enriqueta, Melero, Ignacio, Montuenga, Luis M
Format:	Journal Article
Language:	English
Published:	United States Rockefeller University Press 05-12-2022
Subjects:	Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - pathology Humans Lung Neoplasms - drug therapy Lung Neoplasms - pathology Receptor-Interacting Protein Serine-Threonine Kinases - metabolism Serine Solid Tumors T-Lymphocytes - metabolism Threonine TOR Serine-Threonine Kinases - metabolism Tumor Necrosis Factor-alpha - metabolism Tyrosine
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Summary:	Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Disclosures: R. Thomas reported grants from Roche, personal fees from PearlRiver, and “other” from PearlRiver, Centessa, and Epiphanes outside the submitted work. J. Frigola reported grants from Merck Healthcare KGaA during the conduct of the study. A. Calvo reported grants from AstraZeneca and PharmaMar outside the submitted work. E. Felip reported other from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman - La Roche, GlaxoSmithKline, Ipsen, Janssen, Medical Trends, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, PeerVoice, Peptomyc, Pfizer, Sanofi, Springer, Takeda, TouchTime, Fundación Merck Salud, Grant for Oncology Innovation and Merck, Healthcare KGaA, and Grifols (Independent Member of the Board) outside the submitted work. I. Melero reported personal fees from AstraZeneca, Pharmamar, Roche, and Genmab; grants from AstraZeneca, BMS, Genmab, and Roche; and personal fees from Merus, F-star, Numab, Amunix, Third Rock, and Pieris outside the submitted work. L.M. Montuenga reported grants from AstraZeneca, Bristol Myers Squibb, and Serum. No other disclosures were reported.
ISSN:	0022-1007 1540-9538
DOI:	10.1084/jem.20220726