Abstract 3989: DSTYK inhibition sensitizes lung cancer cells to immunotherapy by collapsing cytoprotective autophagy and destroying mitochondrial wellness
Authors: Valencia Karmele , Echepare Mirari , Pasquier Andrea , Teijeira Alvaro , Bertolo Cristina , Sainz Cristina , Bosco Graziella , Thomas Roman K. , Agorreta Jackeline , Lopez-Picazo Jose Maria , Frigola Joan , Amat Ramon , Calvo Alfonso , Felip Enriqueta , Montuenga Luis M. 
Published: June 2022

Abstract
Lung cancer is the leading cause of cancer-related death worldwide. The incidence and mortality associated to lung cancer is a major challenge of the Public Health Policy in advanced societies. Although the great effort has been done in NSCLC therapeutic strategies, there are still many NSCLC patients who cannot benefit either from molecular targeted or immune related therapies. Here, we identified DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel candidate with a crucial role in NSCLC. According to data obtained from the TCGA, genomic alterations (mainly copy number alterations and mutations) of DSTYK are present in 40% of lung cancer patients, from which 4.7% LUAD and 3.4% LUSC correspond to copy number (CN) amplification (more than 3 genomic copies). Besides, DSTYK amplification is found to be a poor prognostic factor in lung cancer patients. Accordingly, high expression of DSTYK predicted both, a lower overall survival (OS) and poorer progression free survival (PFS). We next depleted DSTYK expression in both murine and human NSCLC cell lines. DSTYK abrogation prevented cytoprotective autophagy via mTOR regulation, accumulating LC3 and p-P62. In addition, DSTYK inhibition impaired lysosomal biogenesis and maturation, which contributed to dysfunctional autophagy. Furthermore, DSTYK depleted cells showed increased ROS levels caused by depolarized and damaged mitochondria. All together, these results demonstrate that knockdown of DSTYK promoted a dramatic reduction of mitophagy.As it has been shown that autophagy in cancer cells can limit antitumor immunity, we evaluated the role of immune-mediated tumor cell killing in an altered DSTYK context. We found that inhibition of DSTYK sensitized lung cancer cells to T cell–mediated cytotoxicity, via TNF-ɑ. More importantly, immunocompetent mouse models transplanted with DSTYK-inhibited tumors were sensitized to ɑnti-PD1 treatment.Finally, in a cohort of NSCLC patients that underwent immunotherapy (n=40), DSTYK amplification predicted resistance to the treatment, showing poorer PFS rates. The time to progression for DSTYK amplified patients was on average, around 50% faster than that for non-DSTYK altered patients, diminishing from 232 to 114 months.In conclusion, our results support that DSTYK is a new target and that its inhibition could be the base of new therapies, which could benefit a subgroup of NSCLC patients showing genetic amplification, both at early (adjuvant) or late (single or combined treatment) stages of the disease.
Citation Format: Karmele Valencia, Mirari Echepare, Andrea Pasquier, Alvaro Teijeira, Cristina Bertolo, Cristina Sainz, Graziella Bosco, Roman K. Thomas, Jackeline Agorreta, Jose Maria Lopez-Picazo, Joan Frigola, Ramon Amat, Alfonso Calvo, Enriqueta Felip, Luis M. Montuenga. DSTYK inhibition sensitizes lung cancer cells to immunotherapy by collapsing cytoprotective autophagy and destroying mitochondrial wellness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3989.