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TARGETING ULK1 TO OVERCOME STANDARD TREATMENT RESISTENCE IN DSTYK-AMPLIFIED LUNG CANCER PATIENTS

ABSTRACT: 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-Î± (TNFÎ±) and nuclear factor ÎºB (NF-ÎºB) signaling in tumor cell killing, with autophagy inhibiting TNF-Î±-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-Î±-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-Î±-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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Karmele Valencia

PROVIDER: PXD065330 | JPOST Repository | Tue Jun 23 00:00:00 BST 2026

REPOSITORIES: jPOST

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			Action	DRS
	Phospho%20(STY)Sites.txt	Txt
	Phospho_H2009_Ctrl_01.raw	Raw
	Phospho_H2009_Ctrl_02.raw	Raw
	Phospho_H2009_Ctrl_03.raw	Raw
	Phospho_H2009_Ctrl_04.raw	Raw

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Project description:Purpose:Lung cancer is the leading cause of cancer-related death, and non-small cell lung cancer (NSCLC) accounts for almost 80-85% of all lung cancer cases.The transcriptional factor brachyury has been verified to promote tumor cells migrate, invade and metastasis in various types of tumors, whereas divergent roles of brachyury on cell proliferation have been reported in several types of tumor cells. In this study, we attempted to explore the effect of brachyury on the cell cycle progression and proliferation capability of NSCLC cells. Methods: Firstly, we performed RNA-sequence and ChIP-sequence to explore underlying downstream pathways regulated by brachyury. Cell proliferation and colony formation assays were utilized to detect the effect of brachyury on the proliferation ability of two types of lung NSCLC cells: H460 and Calu-1, which represent different brachyury expression levels. Following Cell cycle and cell apoptosis assays were used to investigate the mechanism by which brachyury promotes NSCLC grow and progression. Results: RNA-sequence and ChIP-sequence (ChIP-seq) showed that one of the vital downstream pathways regulated by brachyury involves in cell cycle progression. Through cell proliferation assays and colony formation assays, we found that inhibition of brachyury could decrease the capability of proliferation in H460 cells. We also found that brachyury overexpression could prevent the transition from G0/G1 to S phase in Calu-1 cells, and brachyury knockdown could decrease the transition of G2/M phase in H460 cells. The cell apoptosis assays showed that inhibition of brachyury could promote apoptosis in H460 cells. Conclusion: In this study we demonstrate that brachyury and downstream target genes together involve in tumor cell cycle regulation by inducing accelerated transition through G2/M, promote tumor cell proliferation and inhibit apoptosis in lung NSCLC H460 cells. Targeting brachyury expression could be developed into a promising avenue for the prevention of lung cancer progression.

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TARGETING ULK1 TO OVERCOME STANDARD TREATMENT RESISTENCE IN DSTYK-AMPLIFIED LUNG CANCER PATIENTS

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