{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:04:01Z","timestamp":1787241841895,"version":"build-2736575974"},"reference-count":73,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T00:00:00Z","timestamp":1709596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic cancer is characterized by fibrosis\/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF\/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF\/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF\/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK\/ERK (Ras, Ras\/Raf\/MEK\/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK\/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug\u2019s effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF\/c-MET signaling pathway, trametinib\u2019s mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.<\/jats:p>","DOI":"10.3390\/cancers16051056","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T05:31:19Z","timestamp":1709616679000},"page":"1056","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Pancreatic Cancer Treatment Targeting the HGF\/c-MET Pathway: The MEK Inhibitor Trametinib"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7262-7474","authenticated-orcid":false,"given":"Junyeol","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae Seung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeong Hwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In Rae","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8798-0491","authenticated-orcid":false,"given":"Ji Kon","family":"Ryu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong-Tae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2174-9726","authenticated-orcid":false,"given":"Sang Hyub","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8708-3280","authenticated-orcid":false,"given":"Woo Hyun","family":"Paik","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 03080, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1016\/S0140-6736(14)61396-9","article-title":"40-year trends in an index of survival for all cancers combined and survival adjusted for age and sex for each cancer in England and Wales, 1971\u20132011: A population-based study","volume":"385","author":"Quaresma","year":"2015","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21654","article-title":"Cancer Statistics, 2021","volume":"71","author":"Siegel","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1056\/NEJMoa1011923","article-title":"FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer","volume":"364","author":"Conroy","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine","volume":"369","author":"Ervin","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1158\/1078-0432.CCR-17-2994","article-title":"Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial","volume":"24","author":"Aung","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1136\/gutjnl-2019-318217","article-title":"Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome","volume":"69","author":"Kalimuthu","year":"2020","journal-title":"Gut"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41588-019-0566-9","article-title":"Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution","volume":"52","author":"Kim","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nature16965","article-title":"Genomic analyses identify molecular subtypes of pancreatic cancer","volume":"531","author":"Bailey","year":"2016","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/s41598-019-56826-9","article-title":"Unsupervised class discovery in pancreatic ductal adenocarcinoma reveals cell-intrinsic mesenchymal features and high concordance between existing classification systems","volume":"10","author":"Dijk","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1053\/j.gastro.2018.08.033","article-title":"Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features","volume":"155","author":"Puleo","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s43018-021-00326-1","article-title":"Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment","volume":"3","author":"Falcomata","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1097\/00006676-200410000-00002","article-title":"Desmoplastic reaction in pancreatic cancer: Role of pancreatic stellate cells","volume":"29","author":"Apte","year":"2004","journal-title":"Pancreas"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4266","DOI":"10.1158\/1078-0432.CCR-11-3114","article-title":"The pancreas cancer microenvironment","volume":"18","author":"Feig","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.pan.2020.01.003","article-title":"Pancreatic stellate cells: Aiding and abetting pancreatic cancer progression","volume":"20","author":"Pothula","year":"2020","journal-title":"Pancreatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1158\/0008-5472.CAN-07-5714","article-title":"Cancer-associated stromal fibroblasts promote pancreatic tumor progression","volume":"68","author":"Hwang","year":"2008","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1038\/bjc.2015.478","article-title":"Hepatocyte growth factor inhibition: A novel therapeutic approach in pancreatic cancer","volume":"114","author":"Pothula","year":"2016","journal-title":"Br. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1158\/0008-5472.CAN-07-2477","article-title":"Pancreatic stellate cells: Partners in crime with pancreatic cancer cells","volume":"68","author":"Vonlaufen","year":"2008","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1486","DOI":"10.1038\/s41416-020-0782-1","article-title":"Targeting the HGF\/c-MET pathway in advanced pancreatic cancer: A key element of treatment that limits primary tumour growth and eliminates metastasis","volume":"122","author":"Xu","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.2353\/ajpath.2010.090899","article-title":"Role of pancreatic stellate cells in pancreatic cancer metastasis","volume":"177","author":"Xu","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1158\/1535-7163.MCT-16-0472","article-title":"MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale","volume":"16","author":"Salgia","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_21","first-page":"3138","article-title":"Valproic acid, targets papillary thyroid cancer through inhibition of c-Met signalling pathway","volume":"9","author":"Fu","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2399","DOI":"10.1158\/1535-7163.MCT-16-0452","article-title":"Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment","volume":"16","author":"Rucki","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4238","DOI":"10.1242\/jcs.191684","article-title":"Acid sphingomyelinase is required for cell surface presentation of Met receptor tyrosine kinase in cancer cells","volume":"129","author":"Zhu","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1080\/15384101.2016.1152428","article-title":"Hepatic stellate cell promoted hepatoma cell invasion via the HGF\/c-Met signaling pathway regulated by p53","volume":"15","author":"Liu","year":"2016","journal-title":"Cell Cycle"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37370","DOI":"10.18632\/oncotarget.8276","article-title":"Biomarker development in MET-targeted therapy","volume":"7","author":"Zhang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_26","first-page":"625","article-title":"Dysregulation of HGF\/c-Met signal pathway and their targeting drugs in lung cancer","volume":"17","author":"Li","year":"2014","journal-title":"Zhongguo Fei Ai Za Zhi"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4625","DOI":"10.1038\/s41388-021-01863-w","article-title":"HGF\/c-MET pathway in cancer: From molecular characterization to clinical evidence","volume":"40","author":"Fu","year":"2021","journal-title":"Oncogene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/339155a0","article-title":"Tyrosine kinase receptor indistinguishable from the c-met protein","volume":"339","author":"Giordano","year":"1989","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1038\/nrm3012","article-title":"MET signalling: Principles and functions in development, organ regeneration and cancer","volume":"11","author":"Trusolino","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/s41568-018-0002-y","article-title":"Known and novel roles of the MET oncogene in cancer: A coherent approach to targeted therapy","volume":"18","author":"Comoglio","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_31","first-page":"6417","article-title":"Gene amplification in gastric and esophageal adenocarcinomas","volume":"50","author":"Houldsworth","year":"1990","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1038\/ng0597-68","article-title":"Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas","volume":"16","author":"Schmidt","year":"1997","journal-title":"Nat. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1093\/carcin\/bgu122","article-title":"The role of the hepatocyte growth factor\/c-MET pathway in pancreatic stellate cell-endothelial cell interactions: Antiangiogenic implications in pancreatic cancer","volume":"35","author":"Patel","year":"2014","journal-title":"Carcinogenesis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1517\/14728222.2012.680957","article-title":"Targeting the HGF\/Met signaling pathway in cancer therapy","volume":"16","author":"Cecchi","year":"2012","journal-title":"Expert. Opin. Ther. Targets"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"761","DOI":"10.7150\/jca.17648","article-title":"Role of tumor microenvironment in tumorigenesis","volume":"8","author":"Wang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S0898-6568(01)00192-9","article-title":"Regulation of MAP kinase activity by peptide receptor signalling pathway: Paradigms of multiplicity","volume":"13","author":"Liebmann","year":"2001","journal-title":"Cell Signal"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S0962-8924(03)00104-1","article-title":"How to make tubes: Signaling by the Met receptor tyrosine kinase","volume":"13","author":"Rosario","year":"2003","journal-title":"Trends Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/nature04869","article-title":"Ras, PI(3)K and mTOR signalling controls tumour cell growth","volume":"441","author":"Shaw","year":"2006","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"31277","DOI":"10.1074\/jbc.M300763200","article-title":"Regulation of hypoxia-inducible factor-1alpha protein level during hypoxic conditions by the phosphatidylinositol 3-kinase\/Akt\/glycogen synthase kinase 3beta pathway in HepG2 cells","volume":"278","author":"Mottet","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"19","DOI":"10.2174\/156800908783497122","article-title":"AKT signaling in regulating angiogenesis","volume":"8","author":"Jiang","year":"2008","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1006\/geno.1996.0311","article-title":"Assignment of the hypoxia-inducible factor 1alpha gene to a region of conserved synteny on mouse chromosome 12 and human chromosome 14q","volume":"34","author":"Semenza","year":"1996","journal-title":"Genomics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8581","DOI":"10.1074\/jbc.272.13.8581","article-title":"Characterization of a subset of the basic-helix-loop-helix-PAS superfamily that interacts with components of the dioxin signaling pathway","volume":"272","author":"Hogenesch","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S1535-6108(03)00085-0","article-title":"Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene","volume":"3","author":"Pennacchietti","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1111\/j.1349-7006.2008.00828.x","article-title":"Induction of hepatocyte growth factor activator gene expression under hypoxia activates the hepatocyte growth factor\/c-Met system via hypoxia inducible factor-1 in pancreatic cancer","volume":"99","author":"Kitajima","year":"2008","journal-title":"Cancer Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4816","DOI":"10.1182\/blood-2002-06-1731","article-title":"HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro","volume":"101","author":"Ding","year":"2003","journal-title":"Blood"},{"key":"ref_46","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_47","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/s12094-010-0501-0","article-title":"C-MET as a new therapeutic target for the development of novel anticancer drugs","volume":"12","author":"Canadas","year":"2010","journal-title":"Clin. Transl. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6654","DOI":"10.1158\/0008-5472.CAN-13-0887","article-title":"Intestinal GUCY2C prevents TGF-beta secretion coordinating desmoplasia and hyperproliferation in colorectal cancer","volume":"73","author":"Gibbons","year":"2013","journal-title":"Cancer Res."},{"key":"ref_49","first-page":"627","article-title":"Increase in the circulating level of hepatocyte growth factor in pancreatic cancer patients","volume":"110","author":"Kemik","year":"2009","journal-title":"Bratisl. Lek. Listy"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/BF01213298","article-title":"Hepatocyte growth factor in assessment of acute pancreatitis: Comparison with C-reactive protein and interleukin-6","volume":"32","author":"Ueda","year":"1997","journal-title":"J. Gastroenterol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1007\/s10620-010-1416-x","article-title":"Expression and prognostic significance of CD151, c-Met, and integrin alpha3\/alpha6 in pancreatic ductal adenocarcinoma","volume":"56","author":"Zhu","year":"2011","journal-title":"Dig. Dis. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1245\/s10434-012-2277-7","article-title":"Postoperative prognostic predictors of pancreatic ductal adenocarcinoma: Clinical analysis and immunoprofile on tissue microarrays","volume":"19","author":"Park","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e627","DOI":"10.1038\/cddis.2013.158","article-title":"The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer","volume":"4","author":"Hage","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1158\/1535-7163.MCT-05-0175","article-title":"Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells","volume":"5","author":"Bauer","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Hill, K.S., Gaziova, I., Harrigal, L., Guerra, Y.A., Qiu, S., Sastry, S.K., Arumugam, T., Logsdon, C.D., and Elferink, L.A. (2012). Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8\/CXCL8 in pancreatic cancer. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040420"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.1158\/0008-5472.CAN-05-0946","article-title":"Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice","volume":"65","author":"Bauer","year":"2005","journal-title":"Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8299","DOI":"10.1021\/acs.jmedchem.8b00838","article-title":"6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer","volume":"61","author":"Buckley","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/978-3-642-54490-3_15","article-title":"Trametinib","volume":"201","author":"Zeiser","year":"2014","journal-title":"Recent. Results Cancer Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1007\/s40265-013-0096-1","article-title":"Trametinib: First global approval","volume":"73","author":"Wright","year":"2013","journal-title":"Drugs"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"11133","DOI":"10.1038\/s41598-020-67814-9","article-title":"Beta 1 integrin signaling mediates pancreatic ductal adenocarcinoma resistance to MEK inhibition","volume":"10","author":"Brannon","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_61","first-page":"2251","article-title":"Trametinib: A MEK inhibitor for management of metastatic melanoma","volume":"8","author":"Lugowska","year":"2015","journal-title":"Onco Targets Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/S1470-2045(12)70270-X","article-title":"Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: A phase 1 dose-escalation trial","volume":"13","author":"Infante","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/S1470-2045(12)70269-3","article-title":"Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: A phase 1 dose-escalation trial","volume":"13","author":"Falchook","year":"2012","journal-title":"Lancet Oncol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/nrc4000","article-title":"MEK1 and MEK2 inhibitors and cancer therapy: The long and winding road","volume":"15","author":"Caunt","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Brauswetter, D., Gurbi, B., Varga, A., Varkondi, E., Schwab, R., Banhegyi, G., Fabian, O., Keri, G., Valyi-Nagy, I., and Petak, I. (2017). Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185687"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100131","DOI":"10.1016\/j.xcrm.2020.100131","article-title":"Overcoming Adaptive Resistance to KRAS and MEK Inhibitors by Co-targeting mTORC1\/2 Complexes in Pancreatic Cancer","volume":"1","author":"Brown","year":"2020","journal-title":"Cell Rep. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.21037\/jgo-22-86","article-title":"A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma","volume":"13","author":"Aung","year":"2022","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S1470-2045(22)00066-3","article-title":"Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: An open-label, randomised, controlled, phase 2 trial","volume":"23","author":"Zhu","year":"2022","journal-title":"Lancet Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1016\/j.ejca.2014.04.024","article-title":"A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas","volume":"50","author":"Infante","year":"2014","journal-title":"Eur. J. Cancer"},{"key":"ref_70","unstructured":"Tai, D. (2024, February 19). Study of Trametinib and Ruxolitinib in Colorectal Cancer and Pancreatic Adenocarcinoma, Available online: https:\/\/clinicaltrials.gov\/study\/NCT04303403."},{"key":"ref_71","unstructured":"Vasquez, S. (2024, February 20). Combined MEK, STAT3 and PD-1 Inhibition in Metastatic Pancreatic Ductal Adenocarcinoma, Available online: https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT05440942."},{"key":"ref_72","unstructured":"Sharry, S. (2024, February 19). Trametinib and Hydroxychloroquine in Treating Patients with Pancreatic Cancer (THREAD), Available online: https:\/\/clinicaltrials.gov\/study\/NCT03825289."},{"key":"ref_73","unstructured":"Duffy, A. (2024, March 03). PaTcH Study: A Phase 2 Study of Trametinib and Hydroxychloroquine in Patients with Metastatic Refractory Pancreatic Cancer (PaTcH), Available online: https:\/\/clinicaltrials.gov\/study\/NCT05518110."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/5\/1056\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:09:27Z","timestamp":1760105367000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/5\/1056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,5]]},"references-count":73,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["cancers16051056"],"URL":"https:\/\/doi.org\/10.3390\/cancers16051056","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,5]]}}}