Universität zu Köln

Valencia, Karmele ORCID: 0000-0002-2882-7427, Echepare, Mirari, Teijeira, Alvaro ORCID: 0000-0002-7339-4464, Pasquier, Andrea, Bertolo, Cristina, Sainz, Cristina, Tamayo, Ibon, Picabea, Benat, Bosco, Graziella ORCID: 0000-0001-6601-4518, Thomas, Roman, Agorreta, Jackeline, Lopez-Picazo, Jose Maria ORCID: 0000-0002-8814-3000, Frigola, Joan, Amat, Ramon, Calvo, Alfonso ORCID: 0000-0003-4074-4242, Felip, Enriqueta, Melero, Ignacio ORCID: 0000-0002-1360-348X and Montuenga, Luis M. (2022). DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity. J. Exp. Med., 219 (12). NEW YORK: ROCKEFELLER UNIV PRESS. ISSN 1540-9538

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Abstract

Valencia et al. show DSTYK, a dual serine/threonine and tyrosine kinase, altered in lung cancer and associated with poor clinical outcome. DSTYK controls cellular processes encompassing cytoprotective autophagy and mitochondrial fitness and its ablation sensitizes cancer cells to T cell-mediated killing. 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-alpha-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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Valencia, Karmele UNSPECIFIED orcid.org/0000-0002-2882-7427 UNSPECIFIED Echepare, Mirari UNSPECIFIED UNSPECIFIED UNSPECIFIED Teijeira, Alvaro UNSPECIFIED orcid.org/0000-0002-7339-4464 UNSPECIFIED Pasquier, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Bertolo, Cristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Sainz, Cristina UNSPECIFIED UNSPECIFIED UNSPECIFIED Tamayo, Ibon UNSPECIFIED UNSPECIFIED UNSPECIFIED Picabea, Benat UNSPECIFIED UNSPECIFIED UNSPECIFIED Bosco, Graziella UNSPECIFIED orcid.org/0000-0001-6601-4518 UNSPECIFIED Thomas, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Agorreta, Jackeline UNSPECIFIED UNSPECIFIED UNSPECIFIED Lopez-Picazo, Jose Maria UNSPECIFIED orcid.org/0000-0002-8814-3000 UNSPECIFIED Frigola, Joan UNSPECIFIED UNSPECIFIED UNSPECIFIED Amat, Ramon UNSPECIFIED UNSPECIFIED UNSPECIFIED Calvo, Alfonso UNSPECIFIED orcid.org/0000-0003-4074-4242 UNSPECIFIED Felip, Enriqueta UNSPECIFIED UNSPECIFIED UNSPECIFIED Melero, Ignacio UNSPECIFIED orcid.org/0000-0002-1360-348X UNSPECIFIED Montuenga, Luis M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-690282
DOI:	10.1084/jem.20220726
Journal or Publication Title:	J. Exp. Med.
Volume:	219
Number:	12
Date:	2022
Publisher:	ROCKEFELLER UNIV PRESS
Place of Publication:	NEW YORK
ISSN:	1540-9538
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language AUTOPHAGY; INVASION; ADENOCARCINOMAS; STATISTICS; KINASES; MTORC1 Multiple languages Immunology; Medicine, Research & Experimental Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69028