{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:48:45Z","timestamp":1792273725737,"version":"4.4.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:00:00Z","timestamp":1792195200000},"content-version":"vor","delay-in-days":31,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA157595; P30CA023074 (Cancer Center Support Grant)"],"award-info":[{"award-number":["R01CA157595; P30CA023074 (Cancer Center Support Grant)"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Amino Acids"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Oncogenic mutations in the K-RAS small GTPase occur in more than 90% of human PDACs and cause dysregulation of multiple metabolic pathways, including polyamine metabolism. The goal of this study was to determine whether blocking polyamine synthesis with the irreversible inhibitor \u03b1-difluoromethylornithine (DFMO) provides a valid approach to targeting metabolic dependency in mutant K-RAS pancreatic tumors, compared with direct suppression of the oncogenic K-RAS protein. The anti-tumor activity of DFMO was evaluated\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    in the MIA PaCa-2 pancreatic cell line (\n                    <jats:italic>K-RAS<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>G12C<\/jats:italic>\n                    <\/jats:sup>\n                    ) and its isogenic clonally selected line M-27, which does not express a functional GTP-bound RAS protein. MIA PaCa-2 and M-27 cells had comparable intracellular polyamine levels, and DFMO treatment effectively suppressed total polyamine levels in both cell lines (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). DFMO reduced the protein levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1\/2) and RAS-like small GTPase A (RalA) but induced the phosphoinositide 3-phosphate kinase (PI3K) signaling pathway. Additionally, the intracellular levels of K-RAS and hypusinated eukaryotic initiation factor 5\u00a0A (eIF5A\n                    <jats:sup>Hyp<\/jats:sup>\n                    ) proteins were suppressed in DFMO-treated MIA PaCa-2 cells. DFMO therapy regimen (500\u00a0mg\/kg\/day by oral gavage) significantly improved survival rates of SCID mice with orthotopically implanted MIA PaCa-2 cell line (MIA PaCa-2 control vs. MIA PaCa-2 DFMO,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0184), with median survival time comparable to animals implanted with M-27 cell line (MIA PaCa-2 control vs. M-27 control,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0204). DFMO treatment did not significantly improve survival of mice bearing M-27 tumors (M-27 control vs. M-27 DFMO,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.6055). These data indicate that DFMO treatment suppresses pancreatic tumorigenesis driven by the mutant\n                    <jats:italic>K-RAS<\/jats:italic>\n                    oncogene similarly to the targeted elimination of the active GTP-bound RAS protein.\n                  <\/jats:p>","DOI":"10.1007\/s00726-026-03559-5","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T11:43:34Z","timestamp":1789559014000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells"],"prefix":"10.1007","volume":"58","author":[{"given":"Hwudaurw","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David E.","family":"Stringer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene W.","family":"Gerner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8096-1340","authenticated-orcid":false,"given":"Natalia A.","family":"Ignatenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"3559_CR1","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","volume":"384","author":"MM Awad","year":"2021","unstructured":"Awad MM, Liu S, Rybkin II, Arbour KC, Dilly J, Zhu VW, Johnson ML, Heist RS, Patil T, Riely GJ, Jacobson JO, Yang X, Persky NS, Root DE, Lowder KE, Feng H, Zhang SS, Haigis KM, Hung YP, Sholl LM, Wolpin BM, Wiese J, Christiansen J, Lee J, Schrock AB, Lim LP, Garg K, Li M, Engstrom LD, Waters L, Lawson JD, Olson P, Lito P, Ou SI, Christensen JG, Janne PA, Aguirre AJ (2021) Acquired Resistance to KRAS(G12C) Inhibition in Cancer. N Engl J Med 384:2382\u20132393","journal-title":"N Engl J Med"},{"key":"3559_CR2","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1126\/science.6775372","volume":"210","author":"CJ Bacchi","year":"1980","unstructured":"Bacchi CJ, Nathan HC, Hutner SH, McCann PP, Sjoerdsma A (1980) Polyamine metabolism: a potential therapeutic target in trypanosomes. Science 210:332\u2013334","journal-title":"Science"},{"key":"3559_CR3","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1158\/1940-6207.CAPR-09-0096","volume":"3","author":"HH Bailey","year":"2010","unstructured":"Bailey HH, Kim K, Verma AK, Sielaff K, Larson PO, Snow S, Lenaghan T, Viner JL, Douglas J, Dreckschmidt NE, Hamielec M, Pomplun M, Sharata HH, Puchalsky D, Berg ER, Havighurst TC, Carbone PP (2010) A randomized, double-blind, placebo-controlled phase 3 skin cancer prevention study of {alpha}-difluoromethylornithine in subjects with previous history of skin cancer. Cancer Prev Res (Phila Pa) 3:35\u201347","journal-title":"Cancer Prev Res (Phila Pa)"},{"key":"3559_CR4","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/s43018-019-0016-8","volume":"1","author":"D Bar-Sagi","year":"2020","unstructured":"Bar-Sagi D, Knelson EH, Sequist LV (2020) A bright future for KRAS inhibitors. Nat Cancer 1:25\u201327","journal-title":"Nat Cancer"},{"key":"3559_CR5","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0304-3835(82)90113-6","volume":"17","author":"O Black Jr","year":"1982","unstructured":"Black O Jr., Chang BK (1982) Ornithine decarboxylase enzyme activity in human and hamster pancreatic tumor cell lines. Cancer Lett 17:87\u201393","journal-title":"Cancer Lett"},{"key":"3559_CR6","doi-asserted-by":"publisher","first-page":"1845","DOI":"10.1038\/s41388-017-0100-4","volume":"37","author":"V Fendrich","year":"2018","unstructured":"Fendrich V, Jendryschek F, Beeck S, Albers M, Lauth M, Esni F, Heeger K, Dengler J, Slater EP, Holler JPN, Baier A, Bartsch DK, Waldmann J (2018) Genetic and pharmacologic abrogation of Snail1 inhibits acinar-to-ductal metaplasia in precursor lesions of pancreatic ductal adenocarcinoma and pancreatic injury. Oncogene 37:1845\u20131856","journal-title":"Oncogene"},{"key":"3559_CR7","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.str.2010.05.013","volume":"18","author":"RB Fenwick","year":"2010","unstructured":"Fenwick RB, Campbell LJ, Rajasekar K, Prasannan S, Nietlispach D, Camonis J, Owen D, Mott HR (2010) The RalB-RLIP76 complex reveals a novel mode of ral-effector interaction. Structure 18: 985\u2009\u2013\u200995","journal-title":"Structure"},{"key":"3559_CR9","doi-asserted-by":"crossref","first-page":"6671","DOI":"10.1158\/0008-5472.CAN-14-1031","volume":"74","author":"K Fujimura","year":"2014","unstructured":"Fujimura K, Wright T, Strnadel J, Kaushal S, Metildi C, Lowy AM, Bouvet M, Kelber JA, Klemke RL (2014) A hypusine-eIF5A-PEAK1 switch regulates the pathogenesis of pancreatic cancer. Cancer Res 74:6671\u20136681","journal-title":"Cancer Res"},{"key":"3559_CR8","doi-asserted-by":"crossref","first-page":"29907","DOI":"10.1074\/jbc.M115.687418","volume":"290","author":"K Fujimura","year":"2015","unstructured":"Fujimura K, Choi S, Wyse M, Strnadel J, Wright T, Klemke R (2015) Eukaryotic Translation Initiation Factor 5A (EIF5A) Regulates Pancreatic Cancer Metastasis by Modulating RhoA and Rho-associated Kinase (ROCK) Protein Expression Levels. J Biol Chem 290:29907\u201329919","journal-title":"J Biol Chem"},{"key":"3559_CR10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1002\/mc.10043","volume":"34","author":"KE Fultz","year":"2002","unstructured":"Fultz KE, Gerner EW (2002) APC-dependent regulation of ornithine decarboxylase in human colon tumor cells. Mol Carcinog 34:10\u201318","journal-title":"Mol Carcinog"},{"key":"3559_CR11","doi-asserted-by":"publisher","first-page":"781","DOI":"10.1038\/nrc1454","volume":"4","author":"EW Gerner","year":"2004","unstructured":"Gerner EW, Meyskens FL, Jr (2004) Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 4:781\u2013792","journal-title":"Nat Rev Cancer"},{"key":"3559_CR12","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1021\/acs.molpharmaceut.7b00718","volume":"15","author":"SB Gitto","year":"2018","unstructured":"Gitto SB, Pandey V, Oyer JL, Copik AJ, Hogan FC, Phanstiel O, Altomare DA (2018) Difluoromethylornithine Combined with a Polyamine Transport Inhibitor Is Effective against Gemcitabine Resistant Pancreatic Cancer. Mol Pharm 15:369\u2013376","journal-title":"Mol Pharm"},{"key":"3559_CR13","doi-asserted-by":"crossref","first-page":"21648","DOI":"10.1038\/srep21648","volume":"6","author":"R Gradiz","year":"2016","unstructured":"Gradiz R, Silva HC, Carvalho L, Botelho MF, Mota-Pinto A (2016) MIA PaCa-2 and PANC-1 - pancreas ductal adenocarcinoma cell lines with neuroendocrine differentiation and somatostatin receptors. Sci Rep 6:21648","journal-title":"Sci Rep"},{"key":"3559_CR15","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1126\/science.281.5382.1509","volume":"281","author":"TC He","year":"1998","unstructured":"He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509\u20131512","journal-title":"Science"},{"issue":"1","key":"3559_CR14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3892\/or.2023.8666","volume":"51","author":"J He","year":"2024","unstructured":"He J, Bugde P, Li J, Biswas R, Li S, Yang X, Tian F, Wu Z, Li Y (2024) Multidrug resistance protein 5 affects cell proliferation, migration and gemcitabine sensitivity in pancreatic cancer MIA Paca\u20132 and PANC\u20131 cells. Oncol Rep 51(1):7","journal-title":"Oncol Rep"},{"key":"3559_CR16","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1038\/s41586-024-07205-6","volume":"629","author":"M Holderfield","year":"2024","unstructured":"Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, Dinglasan N, Wang Y, Lai LP, Cai S, Jiang L, Nasholm N, Shifrin N, Blaj C, Shah H, Evans JW, Montazer N, Lai O, Shi J, Ahler E, Quintana E, Chang S, Salvador A, Marquez A, Cregg J, Liu Y, Milin A, Chen A, Ziv TB, Parsons D, Knox JE, Klomp JE, Roth J, Rees M, Ronan M, Cuevas-Navarro A, Hu F, Lito P, Santamaria D, Aguirre AJ, Waters AM, Der CJ, Ambrogio C, Wang Z, Gill AL, Koltun ES, Smith JAM, Wildes D, Singh M (2024) Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature 629:919\u2013926","journal-title":"Nature"},{"key":"3559_CR17","first-page":"89","volume":"64","author":"DM Hougaard","year":"1986","unstructured":"Hougaard DM, Larsson LI (1986) Localization and possible function of polyamines in protein and peptide secreting cells. Med Biol 64:89\u201394","journal-title":"Med Biol"},{"key":"3559_CR18","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41575-023-00840-w","volume":"21","author":"ZI Hu","year":"2024","unstructured":"Hu ZI, O\u2019Reilly EM (2024) Therapeutic developments in pancreatic cancer. Nat Rev Gastroenterol Hepatol 21:7\u201324","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"3559_CR19","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41392-021-00780-4","volume":"6","author":"L Huang","year":"2021","unstructured":"Huang L, Guo Z, Wang F, Fu L (2021) KRAS mutation: from undruggable to druggable in cancer. Signal Transduct Target Ther 6:386","journal-title":"Signal Transduct Target Ther"},{"key":"3559_CR20","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1042\/BST0350326","volume":"35","author":"MT Hyvonen","year":"2007","unstructured":"Hyvonen MT, Merentie M, Uimari A, Keinanen TA, Janne J, Alhonen L (2007) Mechanisms of polyamine catabolism-induced acute pancreatitis. Biochem Soc Trans 35:326\u2013330","journal-title":"Biochem Soc Trans"},{"key":"3559_CR21","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1006\/bbrc.2000.2601","volume":"271","author":"K Igarashi","year":"2000","unstructured":"Igarashi K, Kashiwagi K (2000) Polyamines: mysterious modulators of cellular functions. Biochem Biophys Res Commun 271:559\u2013564","journal-title":"Biochem Biophys Res Commun"},{"key":"3559_CR22","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/j.cell.2005.01.014","volume":"120","author":"SM Johnson","year":"2005","unstructured":"Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell 120: 635\u2009\u2013\u200947","journal-title":"Cell"},{"key":"3559_CR23","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/s10555-020-09952-0","volume":"40","author":"AA Khan","year":"2021","unstructured":"Khan AA, Liu X, Yan X, Tahir M, Ali S, Huang H (2021) An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev 40:245\u2013272","journal-title":"Cancer Metastasis Rev"},{"key":"3559_CR24","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1016\/j.jtho.2021.04.015","volume":"16","author":"T Koga","year":"2021","unstructured":"Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, Chiba M, Shimoji M, Takemoto T, Arita T, Gmachl M, Hofmann MH, Soh J, Mitsudomi T (2021) KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From In Vitro Experiments. J Thorac Oncol 16:1321\u20131332","journal-title":"J Thorac Oncol"},{"key":"3559_CR25","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.3892\/ijo.2013.1835","volume":"42","author":"DL Koomoa","year":"2013","unstructured":"Koomoa DL, Geerts D, Lange I, Koster J, Pegg AE, Feith DJ, Bachmann AS (2013) DFMO\/eflornithine inhibits migration and invasion downstream of MYCN and involves p27Kip1 activity in neuroblastoma. Int J Oncol 42:1219\u20131228","journal-title":"Int J Oncol"},{"key":"3559_CR26","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1158\/1940-6207.CAPR-12-0233","volume":"5","author":"SM Kreul","year":"2012","unstructured":"Kreul SM, Havighurst T, Kim K, Mendonca EA, Wood GS, Snow S, Borich A, Verma A, Bailey HH (2012) A Phase III Skin Cancer Chemoprevention Study of DFMO: Long-term Follow-up of Skin Cancer Events and Toxicity. Cancer Prev Res (Phila) 5:1368\u20131374","journal-title":"Cancer Prev Res (Phila)"},{"key":"3559_CR27","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1002\/cbin.10039","volume":"37","author":"M Liu","year":"2013","unstructured":"Liu M, Zhu H, Yang S, Wang Z, Bai J, Xu N (2013) c-Myc suppressed E-cadherin through miR-9 at the post-transcriptional level. Cell Biol Int 37:197\u2013202","journal-title":"Cell Biol Int"},{"key":"3559_CR28","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1097\/00006676-199811000-00001","volume":"17","author":"DS Longnecker","year":"1998","unstructured":"Longnecker DS, Terhune PG (1998) What is the true rate of K-ras mutation in carcinoma of the pancreas? Pancreas 17:323\u2013324","journal-title":"Pancreas"},{"key":"3559_CR29","doi-asserted-by":"crossref","first-page":"e0181532","DOI":"10.1371\/journal.pone.0181532","volume":"12","author":"L Lu","year":"2017","unstructured":"Lu L, Zeng J (2017) Evaluation of K-ras and p53 expression in pancreatic adenocarcinoma using the cancer genome atlas. PLoS ONE 12:e0181532","journal-title":"PLoS ONE"},{"key":"3559_CR30","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1053\/j.seminoncol.2021.02.003","volume":"48","author":"J Luo","year":"2021","unstructured":"Luo J (2021) KRAS mutation in pancreatic cancer. Semin Oncol 48:10\u201318","journal-title":"Semin Oncol"},{"key":"3559_CR31","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1007\/s10585-004-2724-3","volume":"21","author":"A Manni","year":"2004","unstructured":"Manni A, Washington S, Mauger D, Hackett DA, Verderame MF (2004) Cellular mechanisms mediating the anti-invasive properties of the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) in human breast cancer cells. Clin Exp Metastasis 21:461\u2013467","journal-title":"Clin Exp Metastasis"},{"key":"3559_CR32","doi-asserted-by":"publisher","first-page":"13269","DOI":"10.1038\/srep13269","volume":"5","author":"TL Mastracci","year":"2015","unstructured":"Mastracci TL, Robertson MA, Mirmira RG, Anderson RM (2015) Polyamine biosynthesis is critical for growth and differentiation of the pancreas. Sci Rep 5:13269","journal-title":"Sci Rep"},{"key":"3559_CR33","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1158\/1940-6207.CAPR-08-0042","volume":"1","author":"FL Meyskens Jr.","year":"2008","unstructured":"Meyskens FL Jr., McLaren CE, Pelot D, Fujikawa-Brooks S, Carpenter PM, Hawk E, Kelloff G, Lawson MJ, Kidao J, McCracken J, Albers CG, Ahnen DJ, Turgeon DK, Goldschmid S, Lance P, Hagedorn CH, Gillen DL, Gerner EW (2008) Difluoromethylornithine plus sulindac for the prevention of sporadic colorectal adenomas: a randomized placebo-controlled, double-blind trial. Cancer Prev Res (Phila Pa) 1:32\u201338","journal-title":"Cancer Prev Res (Phila Pa)"},{"key":"3559_CR34","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1016\/0140-6736(92)92180-N","volume":"340","author":"F Milord","year":"1992","unstructured":"Milord F, Pepin J, Loko L, Ethier L, Mpia B (1992) Efficacy and toxicity of eflornithine for treatment of Trypanosoma brucei gambiense sleeping sickness. Lancet 340:652\u2013655","journal-title":"Lancet"},{"key":"3559_CR35","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1158\/1940-6207.CAPR-14-0176","volume":"7","author":"A Mohammed","year":"2014","unstructured":"Mohammed A, Janakiram NB, Madka V, Ritchie RL, Brewer M, Biddick L, Patlolla JM, Sadeghi M, Lightfoot S, Steele VE, Rao CV (2014) Eflornithine (DFMO) prevents progression of pancreatic cancer by modulating ornithine decarboxylase signaling. Cancer Prev Res (Phila) 7:1198\u20131209","journal-title":"Cancer Prev Res (Phila)"},{"key":"3559_CR36","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1007\/s004280100474","volume":"439","author":"PS Moore","year":"2001","unstructured":"Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR, Gress T, Bassi C, Kloppel G, Kalthoff H, Ungefroren H, Lohr M, Scarpa A (2001) Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4\/Smad4. Virchows Arch 439:798\u2013802","journal-title":"Virchows Arch"},{"key":"3559_CR37","doi-asserted-by":"crossref","first-page":"51743","DOI":"10.1074\/jbc.M308702200","volume":"278","author":"S Moskalenko","year":"2003","unstructured":"Moskalenko S, Tong C, Rosse C, Mirey G, Formstecher E, Daviet L, Camonis J, White MA (2003) Ral GTPases regulate exocyst assembly through dual subunit interactions. J Biol Chem 278:51743\u201351748","journal-title":"J Biol Chem"},{"key":"3559_CR38","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4103\/0976-0105.177703","volume":"7","author":"AB Nair","year":"2016","unstructured":"Nair AB, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27\u201331","journal-title":"J Basic Clin Pharm"},{"issue":"24","key":"3559_CR39","doi-asserted-by":"crossref","first-page":"13175","DOI":"10.3390\/ijms222413175","volume":"22","author":"SP Nakkina","year":"2021","unstructured":"Nakkina SP, Gitto SB, Beardsley JM, Pandey V, Rohr MW, Parikh JG, Phanstiel O, Altomare DA (2021) DFMO Improves survival and increases immune cell infiltration in association with MYC downregulation in the pancreatic tumor microenvironment. Int J Mol Sci 22(24):13175","journal-title":"Int J Mol Sci"},{"key":"3559_CR40","doi-asserted-by":"crossref","unstructured":"O\u2019Reilly EM, Wainberg ZA, Hendifar AE, Borad MJ, Pietrantonio F, Pant S, Hammel P, Cremolini C, Manji GA, Oberstein PE, Garrido-Laguna I, Springfeld C, Azad NS, Ueno M, Chui SY, Zhang Y, Patel H, Lee Y, Salman Z Wolpin BM and R. ASolute 302 Trial Investigators (2026) Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med 395: 325\u2013337","DOI":"10.1056\/NEJMoa2605555"},{"key":"3559_CR41","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1200\/JCO.22.02875","volume":"42","author":"J Oesterheld","year":"2024","unstructured":"Oesterheld J, Ferguson W, Kraveka JM, Bergendahl G, Clinch T, Lorenzi E, Berry D, Wada RK, Isakoff MS, Eslin DE, Brown VI, Roberts W, Zage P, Harrod VL, Mitchell DS, Hanson D and G. L. Saulnier Sholler (2024) Eflornithine as postimmunotherapy maintenance in high-risk neuroblastoma: externally controlled, propensity score-matched survival outcome comparisons. J Clin Oncol 42: 90\u2013102","journal-title":"J Clin Oncol"},{"key":"3559_CR42","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1073\/pnas.96.5.2122","volume":"96","author":"Y Ohta","year":"1999","unstructured":"Ohta Y, Suzuki N, Nakamura S, Hartwig JH, Stossel TP (1999) The small GTPase RalA targets filamin to induce filopodia. Proc Natl Acad Sci U S A 96:2122\u20132128","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3559_CR43","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1038\/nature12796","volume":"503","author":"JM Ostrem","year":"2013","unstructured":"Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548\u2013551","journal-title":"Nature"},{"key":"3559_CR44","first-page":"95","volume":"8","author":"J Padavano","year":"2015","unstructured":"Padavano J, Henkhaus RS, Chen H, Skovan BA, Cui H, Ignatenko NA (2015) Mutant K-RAS Promotes Invasion and Metastasis in Pancreatic Cancer Through GTPase Signaling Pathways. Cancer Growth Metastasis 8:95\u2013113","journal-title":"Cancer Growth Metastasis"},{"key":"3559_CR45","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1093\/jb\/mvj034","volume":"139","author":"MH Park","year":"2006","unstructured":"Park MH (2006) The post-translational synthesis of a polyamine-derived amino acid, hypusine, in the eukaryotic translation initiation factor 5A (eIF5A). J Biochem 139:161\u2013169","journal-title":"J Biochem"},{"key":"3559_CR46","doi-asserted-by":"crossref","first-page":"18710","DOI":"10.1074\/jbc.TM118.003341","volume":"293","author":"MH Park","year":"2018","unstructured":"Park MH, Wolff EC (2018) Hypusine, a polyamine-derived amino acid critical for eukaryotic translation. J Biol Chem 293:18710\u201318718","journal-title":"J Biol Chem"},{"issue":"Suppl 1","key":"3559_CR47","first-page":"E96","volume":"53","author":"EA Paz","year":"2014","unstructured":"Paz EA, LaFleur B, Gerner EW (2014) Polyamines are oncometabolites that regulate the LIN28\/let-7 pathway in colorectal cancer cells. Mol Carcinog 53(Suppl 1):E96\u2013106","journal-title":"Mol Carcinog"},{"key":"3559_CR48","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1038\/nrc3106","volume":"11","author":"Y Pylayeva-Gupta","year":"2011","unstructured":"Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D (2011) RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 11:761\u2013774","journal-title":"Nat Rev Cancer"},{"key":"3559_CR49","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1016\/j.annonc.2025.01.020","volume":"36","author":"JM de la Riedl","year":"2025","unstructured":"Riedl JM, de la Fece F, Lin JJ, Parseghian C, Kim JE, Matsubara H, Barnes H, Caughey B, Norden BL, Morales-Giron AA, Kushner EW, Ehnstrom S, Nakamura H, Patel PS, Ellis H, Pappas L, Vakaris A, Gainor JF, Kopetz S, Klempner SJ, Parikh AR, Hata AN, Heist RS, Corcoran RB (2025) Genomic landscape of clinically acquired resistance alterations in patients treated with KRAS(G12C) inhibitors. Ann Oncol 36:682\u2013692","journal-title":"Ann Oncol"},{"key":"3559_CR50","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0378-4347(00)84307-8","volume":"221","author":"N Seiler","year":"1980","unstructured":"Seiler N, Knodgen B (1980) High-performance liquid chromatography procedure for the simultaneous determination of the natural polyamines and their monoacetylderivatives. J Chromatogr 221:227\u2013238","journal-title":"J Chromatogr"},{"key":"3559_CR51","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1158\/1055-9965.EPI-07-0658","volume":"17","author":"AR Simoneau","year":"2008","unstructured":"Simoneau AR, Gerner EW, Nagle R, Ziogas A, Fujikawa-Brooks S, Yerushalmi H, Ahlering TE, Lieberman R, McLaren CE, Anton-Culver H, Meyskens FL, Jr (2008) The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: results of a year-long phase IIb randomized placebo-controlled chemoprevention trial. Cancer Epidemiol Biomarkers Prev 17:292\u2013299","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"3559_CR52","doi-asserted-by":"crossref","first-page":"4627","DOI":"10.1158\/1078-0432.CCR-22-3930","volume":"29","author":"H da Singh","year":"2023","unstructured":"Singh H, Keller RB, Kapner KS, Dilly J, Raghavan S, Yuan C, Cohen EF, Tolstorukov M, Andrews E, Brais LK, da Silva A, Perez K, Rubinson DA, Surana R, Giannakis M, Ng K, Clancy TE, Yurgelun MB, Schlechter BL, Clark JW, Shapiro GI, Rosenthal MH, Hornick JL, Nardi V, Li YY, Gupta H, Cherniack AD, Meyerson M, Cleary JM, Nowak JA, Wolpin BM, Aguirre AJ (2023) Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer. Clin Cancer Res 29:4627\u20134643","journal-title":"Clin Cancer Res"},{"key":"3559_CR53","doi-asserted-by":"crossref","first-page":"7290","DOI":"10.1158\/1078-0432.CCR-04-0972","volume":"10","author":"AL Subhi","year":"2004","unstructured":"Subhi AL, Tang B, Balsara BR, Altomare DA, Testa JR, Cooper HS, Hoffman JP, Meropol NJ, Kruger WD (2004) Loss of methylthioadenosine phosphorylase and elevated ornithine decarboxylase is common in pancreatic cancer. Clin Cancer Res 10:7290\u20137296","journal-title":"Clin Cancer Res"},{"key":"3559_CR54","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1126\/science.2821624","volume":"238","author":"M Trahey","year":"1987","unstructured":"Trahey M, McCormick F (1987) A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238:542\u2013545","journal-title":"Science"},{"key":"3559_CR55","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/j.1460-2075.1996.tb00416.x","volume":"15","author":"T Urano","year":"1996","unstructured":"Urano T, Emkey R, Feig LA (1996) Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J 15:810\u2013816","journal-title":"EMBO J"},{"key":"3559_CR56","doi-asserted-by":"crossref","first-page":"606","DOI":"10.3892\/ijo.2016.3804","volume":"50","author":"Y Wang","year":"2017","unstructured":"Wang Y, Kuramitsu Y, Baron B, Kitagawa T, Tokuda K, Akada J, Maehara SI, Maehara Y, Nakamura K (2017) PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. Int J Oncol 50:606\u2013612","journal-title":"Int J Oncol"},{"key":"3559_CR57","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1111\/j.1365-4632.2006.03079.x","volume":"46","author":"JE Wolf Jr","year":"2007","unstructured":"Wolf JE Jr., Shander D, Huber F, Jackson J, Lin CS, Mathes BM, Schrode K, HCl Study Group Eflornithine (2007) Randomized, double-blind clinical evaluation of the efficacy and safety of topical eflornithine HCl 13.9% cream in the treatment of women with facial hair. Int J Dermatol 46:94\u201398","journal-title":"Int J Dermatol"},{"key":"3559_CR58","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/0955-0674(95)80110-3","volume":"7","author":"KM Yamada","year":"1995","unstructured":"Yamada KM, Miyamoto S (1995) Integrin transmembrane signaling and cytoskeletal control. Curr Opin Cell Biol 7:681\u2013689","journal-title":"Curr Opin Cell Biol"},{"key":"3559_CR59","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/ncb3292","volume":"18","author":"HW Yang","year":"2016","unstructured":"Yang HW, Collins SR, Meyer T (2016) Locally excitable Cdc42 signals steer cells during chemotaxis. Nat Cell Biol 18:191\u2013201","journal-title":"Nat Cell Biol"},{"key":"3559_CR60","first-page":"1","volume":"102","author":"A Young","year":"2009","unstructured":"Young A, Lyons J, Miller AL, Phan VT, Alarcon IR, McCormick F (2009) Ras signaling and therapies. Adv Cancer Res 102:1\u201317","journal-title":"Adv Cancer Res"},{"key":"3559_CR61","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.cell.2016.11.059","volume":"168","author":"Y Zhou","year":"2017","unstructured":"Zhou Y, Prakash P, Liang H, Cho KJ, Gorfe AA, Hancock JF (2017) Lipid-Sorting Specificity Encoded in K-Ras Membrane Anchor Regulates Signal Output. Cell 168:239\u2013251","journal-title":"Cell"}],"container-title":["Amino Acids"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00726-026-03559-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00726-026-03559-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00726-026-03559-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:19:52Z","timestamp":1792271992000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00726-026-03559-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3559"],"URL":"https:\/\/doi.org\/10.1007\/s00726-026-03559-5","relation":{},"ISSN":["1438-2199"],"issn-type":[{"value":"1438-2199","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]},"assertion":[{"value":"14 June 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors disclose no conflicts.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The animal study protocol was approved by the Institutional Animal Care and Use Committee of the University of Arizona (protocol number 2021\u2009\u2212\u20090772). The University of Arizona Animal Care facility is AAALAC-accredited and holds an Animal Welfare Assurance #D16-00159 (A-3248-01).","order":2,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":3,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"60"}}