PXD065330

PXD065330 is an original dataset announced via ProteomeXchange.

Title	TARGETING ULK1 TO OVERCOME STANDARD TREATMENT RESISTENCE IN DSTYK-AMPLIFIED LUNG CANCER PATIENTS
Description	The emergence of immunotherapy has significantly advanced the treatment of non-small cell lung cancer (NSCLC), yet acquired resistance remains a critical challenge. Understanding the molecular mechanisms behind tumor cell sensitivity to T-cell killing is essential to overcome resistance and improve treatment outcomes. Previous studies have indicated the roles of T cell-derived tumor necrosis factor-α (TNFα) and nuclear factor κB (NF-κB) signaling in tumor cell killing, with autophagy inhibiting TNF-α-induced apoptosis. Prior research in our lab has identified DSTYK, a dual serine/threonine and tyrosine kinase amplified in NSCLC, as a key regulator of mTOR. DSTYK plays a critical role in preventing TNF-α-mediated CD8+ T cell killing and impairs the response to immunotherapy in non-small cell lung cancer by inhibiting autophagy. However, the specific mechanism by which autophagy constrains TNF-α-dependent apoptosis remains unclear. In this study, we demonstrate that inhibition of DSTYK disrupts ULK1 phosphorylation, leading to RIPK1 autophosphorylation and promoting proapoptotic signaling through TNFR1 complex II. Furthermore, we demonstrated that ULK1 inhibition replicates the effects of DSTYK inhibition, reducing tumorigenic properties and sensitizing cells to apoptosis and necroptosis. In vivo experiments in syngeneic and xenograft mouse models corroborated these findings, showing significant tumor size reduction upon ULK1 inhibition. Inhibiting ULK1 enhances the sensitivity of lung tumors to standard treatments, including paclitaxel and immunotherapy. In NSCLC patients, we show ULK1 expression as a poor prognostic biomarker, closely correlating with the levels of P65 protein, p-RIPK1, and p-MLKL. ULK1 is suggested as a reliable surrogate for DSTYK, and given the absence of a selective DSTYK inhibitor, targeting ULK1 may present a promising therapeutic approach. In conclusion, our study identifies DSTYK as a key regulator of the TNFR1 pathway via ULK1 phosphorylation, suggesting that targeting ULK1 could be a viable therapeutic strategy for sensitizing DSTYK-amplified NSCLC tumors to cell death.
HostingRepository	jPOST
AnnounceDate	2026-06-23
AnnouncementXML	Submission_2026-06-22_08:00:05.378.xml
DigitalObjectIdentifier
ReviewLevel	Non peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joaquin Fernandez-Irigoyen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	S-carboxamidomethyl-L-cysteine; N6-acetyl-L-lysine; 2-pyrrolidone-5-carboxylic acid (Gln); L-methionine sulfoxide
Instrument	instrument

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-23 06:28:07	ID requested
⏵ 1	2026-06-22 08:00:06	announced

Dataset with its publication pending

submitter keyword: Lung cancer, DSTYK, ULK1, RIPK1, autophagy, TNFR1 pathway, apoptosis

Karmele Valencia
lab head
Joaquin Fernandez-Irigoyen
contact affiliation	Navarrabiomed
dataset submitter

jPOST dataset URI

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