Publicaciones científicas

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

28-sep-2022 | Revista: The Journal of Experimental Medicine

Karmele Valencia  1   2   3   4 , Mirari Echepare  1   5   3 , Álvaro Teijeira  2   3   6 , Andrea Pasquier  1   3 , Cristina Bértolo  1 , Cristina Sainz  1   3 , Ibon Tamayo  3   7 , Beñat Picabea  1 , Graziella Bosco  8 , Roman Thomas  8   9   10 , Jackeline Agorreta  1   11 , José María López-Picazo  12 , Joan Frigola  13 , Ramon Amat  13 , Alfonso Calvo  1   5   2   3 , Enriqueta Felip  13   14 , Ignacio Melero  2   3   12 , Luis M Montuenga  1   5   2   3


Abstract

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.

CITA DEL ARTÍCULO  J Exp Med. 2022 Dec 5;219(12):e20220726. doi: 10.1084/jem.20220726. Epub 2022 Sep 28

Nuestros autores

Alfonso Calvo González
Cristina Sainz Zubieta
Ibon Tamayo Uría
Colaborador de Investigación Plataforma Bioinformática
Alfonso Calvo González