{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T20:09:15Z","timestamp":1779912555323,"version":"3.53.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2021,1,31]],"date-time":"2021-01-31T00:00:00Z","timestamp":1612051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Two young cynomolgus macaques (Macaca fascicularis) given a small molecule kinase inhibitor ((S)-4-((2\u2013(5-chloro-2-fluorophenyl)-5-isopropylpyrimidin-4-yl)amino)-N-(2-hydroxypropyl)nicotinamide [SCIO-120]) via nasogastric intubation gavage, once-daily for 21\u2009days at 400\u2009mg\/kg\/day, developed an unusual epithelial proliferative process in the renal parenchyma. Morphological and immunohistochemical characterization of the lesions confirmed an invasive malignant epithelial neoplasm (carcinoma). A similar renal neoplasm was seen in a third macaque after a 14-day exposure to a second kinase inhibitor in the same chemical series ((S) 4-((2\u2013(5-chloro-2-fluorophenyl)-5-methoxypyrimidin-4-yl)amino)-N-cyclopropylnicotinamide [SCIO-974]). Despite remarkably short latency periods, exposure to these kinase inhibitors was likely causally associated with the induction of the renal tumors, as renal carcinomas are exceedingly rare spontaneously in macaques. Both SCIO-120 and SCIO-974 were designed as potent TGF\u03b2R1 inhibitors (IC50s 37 and 39\u2009nM, respectively). SCIO-120 and SCIO-974 inhibited additional kinases, most notably closely related ALK4 (IC50 = 34\u2009 and 20\u2009nM, respectively), c-Jun n-Terminal kinase 3 (JNK3, IC50 = 10 and 20\u2009nM, respectively), and Fms-related tyrosine kinase 1 (29\u2009 and 76\u2009nM, respectively). TGF\u03b2R1 has been specifically implicated in epithelial proliferative disorders, including neoplasia. Neither SCIO-120 nor SCIO-974 was genotoxic based on bacterial reverse mutation and\/or clastogenicity screening assays. The rapid appearance of renal carcinomas in primates following short-term treatment with nongenotoxic kinase inhibitors is remarkable and suggests that the compounds had noteworthy tumor-enhancing effects, hypothetically linked to their TGF\u03b2R1 inhibition activity. These observations have implications for mechanisms of carcinogenesis and TGF\u03b2R1 biology.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa190","type":"journal-article","created":{"date-parts":[[2020,12,22]],"date-time":"2020-12-22T12:20:34Z","timestamp":1608639634000},"page":"51-61","source":"Crossref","is-referenced-by-count":2,"title":["Inhibitors of TGF\u03b2R1\/ALK4\/JNK3\/Flt1 Kinases in Cynomolgus Macaques Lead to the Rapid Induction of Renal Epithelial Tumors"],"prefix":"10.1093","volume":"180","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4524-0510","authenticated-orcid":false,"given":"Vinicius","family":"Carreira","sequence":"first","affiliation":[{"name":"Nonclinical Safety, Janssen R&D, San Diego, California 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M","family":"Standeven","sequence":"additional","affiliation":[{"name":"Nonclinical Safety, Janssen R&D, South San Francisco, California 94080, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Ying","family":"Ma","sequence":"additional","affiliation":[{"name":"Nonclinical Safety, Janssen R&D, San Diego, California 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry","family":"Hardisty","sequence":"additional","affiliation":[{"name":"Experimental Pathology Laboratories (EPL), Sterling, Virginia 20166, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-0962","authenticated-orcid":false,"given":"Samuel M","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3135, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Williams D","family":"Kerns","sequence":"additional","affiliation":[{"name":"Department of Nonclinical Drug Development, Accellient Partners, Evergreen, Colorado, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Snook","sequence":"additional","affiliation":[{"name":"Nonclinical Safety, Janssen R&D, San Diego, California 92121, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,31]]},"reference":[{"key":"2021022816094611000_kfaa190-B1","author":"Axon","year":"2004"},{"key":"2021022816094611000_kfaa190-B2","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/j.1600-0684.1989.tb00410.x","article-title":"An overview of the world literature on spontaneous tumors in nonhuman primates","volume":"18","author":"Beniashvili","year":"1989","journal-title":"J. Med. Primatol"},{"key":"2021022816094611000_kfaa190-B3","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.1158\/0008-5472.CAN-08-4623","article-title":"Progressive tumor formation in mice with conditional deletion of TGF-beta signaling in head and neck epithelia is associated with activation of the PI3K\/Akt pathway","volume":"69","author":"Bian","year":"2009","journal-title":"Cancer Res"},{"key":"2021022816094611000_kfaa190-B4","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1177\/0192623310368981","article-title":"Incidences and range of spontaneous findings in control cynomolgus monkeys (Macaca fascicularis) used in toxicity studies","volume":"38","author":"Chamanza","year":"2010","journal-title":"Toxicol. Pathol"},{"key":"2021022816094611000_kfaa190-B5","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1038\/modpathol.2008.44","article-title":"Renal medullary carcinoma: Rhabdoid features and the absence of INI1 expression as markers of aggressive behavior","volume":"21","author":"Cheng","year":"2008","journal-title":"Mod. Pathol"},{"key":"2021022816094611000_kfaa190-B6","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.jfma.2012.05.003","article-title":"How fast can a choroid plexus papilloma grow?","volume":"113","author":"Chung","year":"2014","journal-title":"J. Formos Med. Assoc"},{"key":"2021022816094611000_kfaa190-B7","doi-asserted-by":"crossref","first-page":"2844","DOI":"10.1002\/cncr.24338","article-title":"Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance","volume":"115","author":"Crispen","year":"2009","journal-title":"Cancer"},{"key":"2021022816094611000_kfaa190-B8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.etp.2006.07.003","article-title":"A review of background findings in cynomolgus monkeys (Macaca fascicularis) from three different geographical origins","volume":"58","author":"Drevon-Gaillot","year":"2006","journal-title":"Exp. Toxicol. Pathol"},{"key":"2021022816094611000_kfaa190-B9","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1038\/nrc2524","article-title":"FLT1 and its ligands VEGFB and PlGF: Drug targets for anti-angiogenic therapy?","volume":"8","author":"Fischer","year":"2008","journal-title":"Nat Rev Cancer"},{"key":"2021022816094611000_kfaa190-B10","doi-asserted-by":"crossref","first-page":"101042831771165","DOI":"10.1177\/1010428317711659","article-title":"Role of JNK signaling in oral cancer: A mini review","volume":"39","author":"Gkouveris","year":"2017","journal-title":"Tumour Biol"},{"key":"2021022816094611000_kfaa190-B11","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1038\/ng.780","article-title":"Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1","volume":"43","author":"Goudie","year":"2011","journal-title":"Nat. Genet"},{"key":"2021022816094611000_kfaa190-B12","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.jcpa.2013.06.005","article-title":"Spontaneously arising concurrent ileocaecal adenocarcinoma and renal pelvis transitional cell carcinoma in a rhesus macaque (Macaca mulatta)","volume":"149","author":"Gumber","year":"2013","journal-title":"J. Comp. Pathol"},{"key":"2021022816094611000_kfaa190-B13","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1097\/PAS.0b013e3182635954","article-title":"Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: Clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship","volume":"36","author":"Gupta","year":"2012","journal-title":"Am. J. Surg. Pathol"},{"key":"2021022816094611000_kfaa190-B14","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"2021022816094611000_kfaa190-B15","first-page":"4479","article-title":"Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway","volume":"9","author":"Herbertz","year":"2015","journal-title":"Drug Des. Devel. Ther"},{"key":"2021022816094611000_kfaa190-B16","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.4161\/cc.6.11.4268","article-title":"TGF-beta receptor I conditional knockout mice develop spontaneous squamous cell carcinoma","volume":"6","author":"Honjo","year":"2007","journal-title":"Cell Cycle"},{"key":"2021022816094611000_kfaa190-B17","first-page":"455","article-title":"Spontaneous lesions in cynomolgus monkeys used in toxicity studies","volume":"41","author":"Ito","year":"1992","journal-title":"Jikken Dobutsu"},{"key":"2021022816094611000_kfaa190-B18","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1201\/9780429504624-10","volume-title":"Toxicologic Pathology: Nonclinical Safety Assessment","author":"Johnson","year":"2018"},{"key":"2021022816094611000_kfaa190-B19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1177\/0300985881018s0610","article-title":"Primary renal tumors in nonhuman primates","volume":"18","author":"Jones","year":"1981","journal-title":"Vet. Pathol"},{"key":"2021022816094611000_kfaa190-B20","doi-asserted-by":"crossref","first-page":"3236","DOI":"10.1200\/JCO.2003.11.524","article-title":"TGFBR16A and cancer risk: A meta-analysis of seven case-control studies","volume":"21","author":"Kaklamani","year":"2003","journal-title":"J. Clin. Oncol"},{"key":"2021022816094611000_kfaa190-B21","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1097\/MPA.0b013e3181fe4031","article-title":"How fast can pancreatic cancer grow? A case of pancreatic carcinoma developed within 5 months after a negative examination to the advanced stage with multiple liver and bone metastases","volume":"40","author":"Ko","year":"2011","journal-title":"Pancreas"},{"key":"2021022816094611000_kfaa190-B22","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1177\/030098587801500418","article-title":"Kidney carcinoma in a male Cynomolgus monkey (Macaca fascicularis)","volume":"15","author":"Kommineni","year":"1978","journal-title":"Vet. Pathol"},{"key":"2021022816094611000_kfaa190-B23","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.yrtph.2015.06.008","article-title":"Comparison of physiologic and pharmacologic parameters in Asian and Mauritius cynomolgus macaques","volume":"73","author":"Kozlosky","year":"2015","journal-title":"Regul. Toxicol. Pharmacol"},{"key":"2021022816094611000_kfaa190-B24","author":"Lowenstine","year":"1986"},{"key":"2021022816094611000_kfaa190-B25","first-page":"92","article-title":"A primer of primate pathology: Lesions and nonlesions","volume":"31","author":"Lowenstine","year":"2003","journal-title":"Toxicol. Pathol"},{"key":"2021022816094611000_kfaa190-B26","first-page":"270","article-title":"Renal carcinoma in an owl monkey (Aotus trivirgatus)","volume":"7","author":"Lund","year":"1970","journal-title":"Pathol. Vet"},{"key":"2021022816094611000_kfaa190-B27","doi-asserted-by":"crossref","first-page":"e90353","DOI":"10.1371\/journal.pone.0090353","article-title":"Phase I study of GC1008 (fresolimumab): A human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma","volume":"9","author":"Morris","year":"2014","journal-title":"PLoS One"},{"key":"2021022816094611000_kfaa190-B28","first-page":"1121","article-title":"Neoplasms of the hematopoietic system in nonhuman primates: Report of one spontaneous tumor and two leukemias induced by procarbazine","volume":"46","author":"O\u2019Gara","year":"1971","journal-title":"J. Natl. Cancer Inst"},{"key":"2021022816094611000_kfaa190-B29","first-page":"2727","article-title":"Type I transforming growth factor beta receptor maps to 9q22 and exhibits a polymorphism and a rare variant within a polyalanine tract","volume":"58","author":"Pasche","year":"1998","journal-title":"Cancer Res"},{"key":"2021022816094611000_kfaa190-B30","first-page":"300","article-title":"TGFBR1 and cancer susceptibility","volume":"125","author":"Pasche","year":"2014","journal-title":"Trans. Am. Clin. Climatol. Assoc"},{"key":"2021022816094611000_kfaa190-B31","doi-asserted-by":"crossref","first-page":"djt369","DOI":"10.1093\/jnci\/djt369","article-title":"TGF-beta: Duality of function between tumor prevention and carcinogenesis","volume":"106","author":"Principe","year":"2014","journal-title":"J. Natl. Cancer Inst"},{"key":"2021022816094611000_kfaa190-B32","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1293\/tox.25.63","article-title":"Histopathology of incidental findings in cynomolgus monkeys (Macaca fascicularis) used in toxicity studies","volume":"25","author":"Sato","year":"2012","journal-title":"J. Toxicol. Pathol"},{"key":"2021022816094611000_kfaa190-B33","first-page":"533","article-title":"Neoplasms and proliferative lesions in 1065 nonhuman primate necropsies","volume":"23","author":"Seibold","year":"1973","journal-title":"Lab. Anim. Sci"},{"key":"2021022816094611000_kfaa190-B34","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1097\/PAP.0000000000000138","article-title":"Clinicopathologic and molecular pathology of collecting duct carcinoma and related renal cell carcinomas","volume":"24","author":"Seo","year":"2017","journal-title":"Adv. Anat. Pathol"},{"key":"2021022816094611000_kfaa190-B35","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1293\/tox.11.85","article-title":"Comparison of spontaneous minor lesions in wild-caught and laboratory-bred monkeys","volume":"11","author":"Shimoi","year":"1998","journal-title":"J. Toxicol. Pathol"},{"key":"2021022816094611000_kfaa190-B36","volume-title":"Atlas of Spontaneous and Chemically Induced Tumors in Nonhuman Primates","author":"Shozo Takayama","year":"2000"},{"key":"2021022816094611000_kfaa190-B37","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1089\/ars.2010.3311","article-title":"The incidence of spontaneous neoplasia in two populations of captive rhesus macaques (Macaca mulatta)","volume":"14","author":"Simmons","year":"2011","journal-title":"Antioxid. Redox. Signal"},{"key":"2021022816094611000_kfaa190-B38","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1097\/PAS.0b013e318299f2d1","article-title":"The International Society of Urological Pathology (ISUP) vancouver classification of renal neoplasia","volume":"37","author":"Srigley","year":"2013","journal-title":"Am. J. Surg. Pathol"},{"key":"2021022816094611000_kfaa190-B39","first-page":"196","article-title":"Nonclinical safety evaluation of a transforming growth factor \u03b2 receptor I kinase inhibitor in fischer 344 rats and beagle dogs","volume":"4","author":"Stauber","year":"2014","journal-title":"J. Clin. Toxicol"},{"key":"2021022816094611000_kfaa190-B40","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3390\/jcm5120109","article-title":"Switching roles of TGF-beta in cancer development: Implications for therapeutic target and biomarker studies","volume":"5","author":"Sun","year":"2016","journal-title":"J. Clin. Med"},{"key":"2021022816094611000_kfaa190-B41","doi-asserted-by":"crossref","first-page":"176","DOI":"10.2183\/pjab.84.176","article-title":"Chemical carcinogenesis studies in nonhuman primates","volume":"84","author":"Takayama","year":"2008","journal-title":"Proc. Jpn. Acad. Ser. B Phys. Biol. Sci."},{"key":"2021022816094611000_kfaa190-B42","doi-asserted-by":"crossref","first-page":"259","DOI":"10.2217\/14796694.5.2.259","article-title":"The TGF-beta paradox in human cancer: An update","volume":"5","author":"Tian","year":"2009","journal-title":"Future Oncol"},{"key":"2021022816094611000_kfaa190-B43","doi-asserted-by":"crossref","first-page":"92","DOI":"10.5858\/2010-0478-RAR.1","article-title":"Immunohistochemical diagnosis of renal neoplasms","volume":"135","author":"Truong","year":"2011","journal-title":"Arch. Pathol. Lab. Med"},{"key":"2021022816094611000_kfaa190-B44","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4251\/wjgo.v4.i1.1","article-title":"Debate about TGFBR1 and the susceptibility to colorectal cancer","volume":"4","author":"Valle","year":"2012","journal-title":"World J. Gastrointest. Oncol."},{"key":"2021022816094611000_kfaa190-B45","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1126\/science.1159397","article-title":"Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer","volume":"321","author":"Valle","year":"2008","journal-title":"Science"},{"key":"2021022816094611000_kfaa190-B46","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s00441-011-1199-1","article-title":"Deconstructing the mechanisms and consequences of TGF-beta-induced EMT during cancer progression","volume":"347","author":"Wendt","year":"2012","journal-title":"Cell Tissue Res"},{"key":"2021022816094611000_kfaa190-B47","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.celrep.2018.09.072","article-title":"Long-term in vitro expansion of epithelial stem cells enabled by pharmacological inhibition of PAK1-ROCK-myosin II and TGF-beta signaling","volume":"25","author":"Zhang","year":"2018","journal-title":"Cell Rep"},{"key":"2021022816094611000_kfaa190-B48","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1007\/s11033-011-1009-6","article-title":"The association of polymorphisms on TGFBR1 and colorectal cancer risk: A meta-analysis","volume":"39","author":"Zhang","year":"2012","journal-title":"Mol. Biol. Rep"},{"key":"2021022816094611000_kfaa190-B49","first-page":"3971","article-title":"TGFBR16A is a potential modifier of migration and invasion in colorectal cancer cells","volume":"15","author":"Zhou","year":"2018","journal-title":"Oncol. Lett"}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfaa190\/36157990\/kfaa190.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/toxsci\/article-pdf\/180\/1\/51\/36405586\/kfaa190.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/toxsci\/article-pdf\/180\/1\/51\/36405586\/kfaa190.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,28]],"date-time":"2021-02-28T16:10:16Z","timestamp":1614528616000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/180\/1\/51\/6112028"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,31]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1,31]]},"published-print":{"date-parts":[[2021,2,26]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfaa190","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,3,1]]},"published":{"date-parts":[[2021,1,31]]}}}