DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity
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
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.
CITATION J Exp Med. 2022 Dec 5;219(12):e20220726. doi: 10.1084/jem.20220726. Epub 2022 Sep 28