TY  - EJOU
AU  - Luo, Lei 
AU  - Guan, Fengju 
AU  - Wang, Zhankun 
AU  - Li, Bin 
AU  - Ding, Xuemei 
AU  - Song, Leilei 
AU  - Sun, Lijiang 

TI  - <i>PARP9</i> Modulates Sunitinib Resistance in Clear Cell Renal Cell Carcinoma via <i>STAT1</i>/<i>IRF1</i> Signaling Pathway
T2  - Oncology Research

PY  - 
VL  - 
IS  - 
SN  - 1555-3906

AB  - <b>Background</b>: Resistance to sunitinib represents a major clinical obstacle in the management of clear cell renal cell carcinoma (ccRCC). This investigation aims to identify genes associated with sunitinib resistance and elucidate potential molecular pathways in ccRCC. <b>Methods</b>: To identify differentially expressed genes (DEGs) in sunitinib-resistant ccRCC cells and their parental cells, bioinformatic analysis was performed on the GSE216494 dataset. Protein-protein interaction (PPI) network and topological analyses pinpointed a hub gene. Sunitinib-resistant A498 and 786-O cell lines were employed for <i>in vitro</i> validation. Sunitinib sensitivity and cell proliferation were evaluated using functional assays, such as colony formation and Cell Counting Kit-8 (CCK-8). Protein interactions and signaling pathway activity are investigated using co-immunoprecipitation (Co-IP), dual-luciferase reporter assays, and immunofluorescence. In resistant cells and patient-derived organoids (PDOs), the therapeutic potential of olaparib, either by itself or in conjunction with sunitinib, was assessed. <b>Results</b>: Sunitinib-resistant cells and patient tissues were shown to exhibit consistent upregulation of poly (ADP-ribose) polymerase 9 (<i>PARP9</i>). <i>PARP9</i> knockdown sensitized resistant cells to sunitinib, suppressing proliferation. Conversely, its overexpression induced resistance in parental cells. Additionally, STAT1 and PARP9 interact to promote nuclear translocation and STAT1 phosphorylation. Activation of the <i>STAT1</i>/<i>IRF1</i> axis further enhanced the expression of <i>ISG15</i> and <i>IFIT1</i>. Olaparib treatment can increase sunitinib-resistant ccRCC cells. Olaparib can weaken the <i>STAT1</i>/<i>IRF1</i> signaling pathway and prevent sunitinib-resistant ccRCC cells from proliferating. Importantly, combination treatment with olaparib and sunitinib showed superior antitumor efficacy in ccRCC PDOs. <b>Conclusion</b>: This study demonstrates that <i>PARP9</i> promotes sunitinib resistance in ccRCC by activating the <i>STAT1</i>/<i>IRF1</i> pathway and upregulating <i>ISG15</i>/<i>IFIT1</i>.
KW  - Clear cell renal cell carcinoma; <i>PARP9</i>; <i>STAT1</i>/<i>IRF1</i> signaling pathway; sunitinib resistance; <i>ISG15</i>

DO  - 10.32604/or.2026.080621