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Patients with advanced RCC require systemic therapies for disease control. Although targeted therapies and immune checkpoint inhibitors have shown therapeutic efficacy, patients eventually succumb to disease progression. Therefore, additional therapies targeting different pathways are needed to provide more therapeutic options for sequential treatment. Our study explored the biological mechanisms and therapeutic outcomes for NPS-1034, a dual MET\/AXL inhibitor, in RCC, both in vivo and in vitro. Our results showed that NPS-1034 can significantly inhibit tumor proliferation and induce cancer cell apoptosis. Besides MET and AXL, known targets of NPS-1034, we identified TNFRSF1A as another target gene inhibited by NPS-1034 via antibody arrays. This was further supported by next-generation sequencing, showing that the TNF signaling pathway is one of the most significant NPS-1034-regulated pathways. Furthermore, one of the identified target genes, GADD45A, responsible for NPS-1034 anticancer properties, was significantly associated with patient survival in RCC. GADD45A expression was significantly upregulated via NPS-1034 and downregulated via TNFRSF1A overexpression. Finally, its therapeutic efficacy was demonstrated in vivo, showing that NPS-1034 significantly alleviated the tumor burden and inhibited cell proliferation in a lung metastatic animal model. In conclusion, we explored the therapeutic mechanism of NPS-1034 and found that it targets not only MET and AXL but also TNFRSF1A. In a lung metastatic animal model, we confirmed that NPS-1034 is a potential candidate for systemic therapy in RCC.<\/jats:p>","DOI":"10.3390\/cells13201713","type":"journal-article","created":{"date-parts":[[2024,10,17]],"date-time":"2024-10-17T08:56:32Z","timestamp":1729155392000},"page":"1713","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["NPS-1034 Exerts Therapeutic Efficacy in Renal Cell Carcinoma Through Multiple Targets of MET, AXL, and TNFRSF1A Signaling in a Metastatic Model"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3158-8690","authenticated-orcid":false,"given":"Ya-Chuan","family":"Chang","sequence":"first","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Te","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ying","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2375-0029","authenticated-orcid":false,"given":"Wen-Wei","family":"Sung","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"},{"name":"Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan"},{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21387","article-title":"Cancer Statistics, 2017","volume":"67","author":"Siegel","year":"2017","journal-title":"CA Cancer J. Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3322\/caac.21820","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Sung, W.W., Ko, P.Y., Chen, W.J., Wang, S.C., and Chen, S.L. (2021). Trends in the kidney cancer mortality-to-incidence ratios according to health care expenditures of 56 countries. Sci. Rep., 11.","DOI":"10.1038\/s41598-020-79367-y"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Sung, W.W., Wang, S.C., Hsieh, T.Y., Ho, C.J., Huang, C.Y., Kao, Y.L., Chen, W.J., and Chen, S.L. (2018). Favorable mortality-to-incidence ratios of kidney Cancer are associated with advanced health care systems. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4698-6"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.semcancer.2012.06.006","article-title":"An overview of renal cell cancer: Pathology and genetics","volume":"23","author":"Moch","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"(2013). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499, 43\u201349.","DOI":"10.1038\/nature12222"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4726","DOI":"10.1158\/1078-0432.CCR-07-4921","article-title":"Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors","volume":"14","author":"Nickerson","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5184","DOI":"10.1200\/JCO.23.01977","article-title":"Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update","volume":"41","author":"Singer","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/S1470-2045(20)30436-8","article-title":"Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): Extended follow-up from a randomised, open-label, phase 3 trial","volume":"21","author":"Powles","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0140-6736(23)00922-4","article-title":"Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): A multicentre, randomised, open-label, phase 3 trial","volume":"402","author":"Pal","year":"2023","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1767","DOI":"10.1056\/NEJMoa2212851","article-title":"Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma","volume":"388","author":"Choueiri","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1200\/JCO.23.01569","article-title":"Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study","volume":"42","author":"Motzer","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100030","DOI":"10.1016\/j.esmoop.2020.100030","article-title":"First-line treatment of metastatic clear cell renal cell carcinoma: A decision-making analysis among experts","volume":"6","author":"Aeppli","year":"2021","journal-title":"ESMO Open"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1159\/000088478","article-title":"VEGF as a key mediator of angiogenesis in cancer","volume":"69","author":"Carmeliet","year":"2005","journal-title":"Oncology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1038\/onc.2015.343","article-title":"Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma","volume":"35","author":"Zhou","year":"2016","journal-title":"Oncogene"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3961","DOI":"10.1158\/1078-0432.CCR-12-0002","article-title":"Rapid Angiogenesis Onset after Discontinuation of Sunitinib Treatment of Renal Cell Carcinoma Patients","volume":"18","author":"Griffioen","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1056\/NEJMoa1510016","article-title":"Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma","volume":"373","author":"Choueiri","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1016\/S0140-6736(07)61904-7","article-title":"Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial","volume":"370","author":"Escudier","year":"2007","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"507","DOI":"10.3322\/caac.21411","article-title":"Treatment of renal cell carcinoma: Current status and future directions","volume":"67","author":"Barata","year":"2017","journal-title":"CA A Cancer J. Clin."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1056\/NEJMoa1303989","article-title":"Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma","volume":"369","author":"Motzer","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1158\/0008-5472.CAN-13-1103","article-title":"MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation","volume":"74","author":"Rho","year":"2014","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9294","DOI":"10.1158\/0008-5472.CAN-05-0993","article-title":"Multiple Roles for the Receptor Tyrosine Kinase Axl in Tumor Formation","volume":"65","author":"Holland","year":"2005","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.cytogfr.2006.04.004","article-title":"Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases","volume":"17","author":"Hafizi","year":"2006","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nri2303","article-title":"Immunobiology of the TAM receptors","volume":"8","author":"Lemke","year":"2008","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1517\/13543770903514137","article-title":"Small molecule c-Met kinase inhibitors: A review of recent patents","volume":"20","author":"Porter","year":"2010","journal-title":"Expert. Opin. Ther. Pat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nrclinonc.2012.71","article-title":"MET: A promising anticancer therapeutic target","volume":"9","author":"Peters","year":"2012","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1038\/nrm1261","article-title":"Met, metastasis, motility and more","volume":"4","author":"Birchmeier","year":"2003","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s10637-013-0039-4","article-title":"NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants","volume":"32","author":"Shin","year":"2014","journal-title":"Investig. New Drugs"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chen, J.T., Wang, S.C., Chen, B.S., Chang, Y.C., Yu, C.Y., Sung, W.W., and Song, T.Y. (2022). NPS-1034 Induce Cell Death with Suppression of TNFR1\/NF-\u03baB Signaling in Testicular Cancer. Medicina, 58.","DOI":"10.3390\/medicina58030355"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wang, S.C., Chang, Y.C., Wu, M.Y., Yu, C.Y., Chen, S.L., and Sung, W.W. (2021). Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer. Cancers, 13.","DOI":"10.3390\/cancers13163933"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.canlet.2022.01.007","article-title":"Chidamide and mitomycin C exert synergistic cytotoxic effects against bladder cancer cells in vitro and suppress tumor growth in a rat bladder cancer model","volume":"530","author":"Wang","year":"2022","journal-title":"Cancer Lett."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41467-018-08074-0","article-title":"AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells","volume":"10","author":"Taniguchi","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3892\/ijmm.2022.5200","article-title":"Role of GADD45A in myocardial ischemia\/reperfusion through mediation of the JNK\/p38 MAPK and STAT3\/VEGF pathways","volume":"50","author":"Wang","year":"2022","journal-title":"Int. J. Mol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Lee, H.W., Seo, H.S., Yeom, S.-Y., Kim, S.-N., Kim, C.R., Park, D.-H., Park, W., Choy, Y.B., Park, C.G., and Seo, S.I. (2022). Cabozantinib-Loaded PLGA Nanoparticles: A Potential Adjuvant Strategy for Surgically Resected High-Risk Non-Metastatic Renal Cell Carcinoma. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012634"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Liu, H., Sun, S., Wang, G., Lu, M., Zhang, X., Wei, X., Gao, X., Huang, C., Li, Z., and Zheng, J. (2021). Tyrosine Kinase Inhibitor Cabozantinib Inhibits Murine Renal Cancer by Activating Innate and Adaptive Immunity. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.663517"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12943-016-0565-8","article-title":"Choosing the right cell line for renal cell cancer research","volume":"15","author":"Brodaczewska","year":"2016","journal-title":"Mol. Cancer"},{"key":"ref_39","first-page":"8","article-title":"What\u2019s new in the WHO 2022 classification of kidney tumours?","volume":"115","author":"Alaghehbandan","year":"2022","journal-title":"Pathologica"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/20\/1713\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:15:03Z","timestamp":1760112903000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/20\/1713"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,17]]},"references-count":39,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["cells13201713"],"URL":"https:\/\/doi.org\/10.3390\/cells13201713","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,17]]}}}