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While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110\u03b1\/\u03b2\/\u03b4\/\u03b3 and mTORC1\/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1\/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib\/Trametinib and Omipalisib\/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib\/Trametinib treatment was significantly more effective than Omipalisib\/SHP099 in reducing implanted tumor growth, and the Omipalisib\/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers.<\/jats:p>","DOI":"10.3390\/cancers17071152","type":"journal-article","created":{"date-parts":[[2025,3,31]],"date-time":"2025-03-31T01:59:36Z","timestamp":1743386376000},"page":"1152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Combined Omipalisib and MAPK Inhibition Suppress PDAC Growth"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7278-3927","authenticated-orcid":false,"given":"Bailey A.","family":"Bye","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jarrid L.","family":"Jack","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Pierce","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2338-3115","authenticated-orcid":false,"given":"Richard McKinnon","family":"Walsh","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Austin E.","family":"Eades","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5581-1220","authenticated-orcid":false,"given":"Prabhakar","family":"Chalise","sequence":"additional","affiliation":[{"name":"Department of Biostatistics and Data Science, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Appolinaire","family":"Olou","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2538-8107","authenticated-orcid":false,"given":"Michael N.","family":"VanSaun","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,29]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1200\/JCO.1997.15.6.2403","article-title":"Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial","volume":"15","author":"Burris","year":"1997","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.ejca.2015.12.026","article-title":"Current standards and new innovative approaches for treatment of pancreatic cancer","volume":"57","author":"Conroy","year":"2016","journal-title":"Eur. J. Cancer"},{"key":"ref_4","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_5","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_6","doi-asserted-by":"crossref","unstructured":"Mustachio, L.M., Chelariu-Raicu, A., Szekvolgyi, L., and Roszik, J. (2021). Targeting KRAS in Cancer: Promising Therapeutic Strategies. Cancers, 13.","DOI":"10.3390\/cancers13061204"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1053\/j.gastro.2019.02.037","article-title":"Real-Time Targeted Genome Profile Analysis of Pancreatic Ductal Adenocarcinomas Identifies Genetic Alterations That Might Be Targeted with Existing Drugs or Used as Biomarkers","volume":"156","author":"Singhi","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/s41392-021-00780-4","article-title":"KRAS mutation: From undruggable to druggable in cancer","volume":"6","author":"Huang","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Vatansever, S., Erman, B., and G\u00fcm\u00fc\u015f, Z.H. (2019). Oncogenic G12D mutation alters local conformations and dynamics of K-Ras. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-48029-z"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1158\/1541-7786.MCR-15-0203","article-title":"Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations","volume":"13","author":"Hunter","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1158\/1078-0432.CCR-21-3074","article-title":"FDA Approval Summary: Sotorasib for KRAS G12C-Mutated Metastatic NSCLC","volume":"28","author":"Nakajima","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Bannoura, S.F., Khan, H.Y., and Azmi, A.S. (2022). KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1013902"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Linehan, A., O\u2019Reilly, M., McDermott, R., and O\u2019Kane, G.M. (2024). Targeting KRAS mutations in pancreatic cancer: Opportunities for future strategies. Front. Med., 11.","DOI":"10.3389\/fmed.2024.1369136"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1016\/j.tibs.2011.03.006","article-title":"The Ras-ERK and PI3K-mTOR pathways: Cross-talk and compensation","volume":"36","author":"Mendoza","year":"2011","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1007\/s00280-013-2121-1","article-title":"PI3K and MEK inhibitor combinations: Examining the evidence in selected tumor types","volume":"71","author":"Britten","year":"2013","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1038\/s41467-017-00942-5","article-title":"Survival of pancreatic cancer cells lacking KRAS function","volume":"8","author":"Muzumdar","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1038\/s41591-023-02321-8","article-title":"Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: The phase 2 ROAR trial","volume":"29","author":"Subbiah","year":"2023","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1056\/NEJMoa1708539","article-title":"Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma","volume":"377","author":"Long","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1634\/theoncologist.2017-0642","article-title":"FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring BRAF V600E Mutations","volume":"23","author":"Odogwu","year":"2018","journal-title":"Oncologist"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1158\/1078-0432.CCR-23-1503","article-title":"FDA Approval Summary: Dabrafenib in combination with trametinib for BRAF V600E mutation-positive low-grade glioma","volume":"30","author":"Barbato","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_22","unstructured":"(2023, November 10). FDA Grants Accelerated Approval to Dabrafenib in Combination with Trametinib for Unresectable or Metastatic Solid Tumors with BRAF V600E Mutation, Available online: https:\/\/www.fda.gov\/drugs\/resources-information-approved-drugs\/fda-grants-accelerated-approval-dabrafenib-combination-trametinib-unresectable-or-metastatic-solid."},{"key":"ref_23","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_24","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1158\/0008-5472.CAN-14-1854","article-title":"Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer","volume":"75","author":"Pettazzoni","year":"2015","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Brauswetter, D., Gurbi, B., Varga, A., V\u00e1rkondi, E., Schwab, R., B\u00e1nhegyi, G., F\u00e1bi\u00e1n, O., K\u00e9ri, G., V\u00e1lyi-Nagy, I., and Pet\u00e1k, I. (2017). Molecular subtype specific efficacy of MEK inhibitors in pancreatic cancers. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185687"},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"102137","DOI":"10.1016\/j.ctrv.2020.102137","article-title":"MEK inhibitor resistance mechanisms and recent developments in combination trials","volume":"92","author":"Kun","year":"2021","journal-title":"Cancer Treat. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/s43018-022-00349-2","article-title":"Translational advances in pancreatic ductal adenocarcinoma therapy","volume":"3","author":"Hosein","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1158\/1078-0432.CCR-15-1665","article-title":"First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies","volume":"22","author":"Munster","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1158\/0008-5472.CAN-18-2861","article-title":"Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in KRAS-Mutant Pancreatic and Colorectal Cancer","volume":"79","author":"Weisner","year":"2019","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1038\/nm.1890","article-title":"Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers","volume":"14","author":"Engelman","year":"2008","journal-title":"Nat. Med."},{"key":"ref_32","first-page":"3065","article-title":"Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer","volume":"118","author":"Carracedo","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1750-2187-5-10","article-title":"Inhibition of PI3K\/AKT and MAPK\/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer","volume":"5","author":"Roy","year":"2010","journal-title":"J. Mol. Signal"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/j.jss.2013.03.052","article-title":"Synergistic inhibition of thyroid cancer by suppressing MAPK\/PI3K\/AKT pathways","volume":"184","author":"Kandil","year":"2013","journal-title":"J. Surg. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1158\/1078-0432.CCR-14-1591","article-title":"Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer","volume":"21","author":"Alagesan","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.canlet.2019.05.037","article-title":"Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel\/gemcitabine chemotherapy response in preclinical models of pancreatic cancer","volume":"459","author":"Awasthi","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1158\/1535-7163.MCT-14-0030","article-title":"Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer","volume":"14","author":"Junttila","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1158\/1078-0432.CCR-14-1814","article-title":"A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1\/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors","volume":"21","author":"Bedard","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1007\/s10637-016-0377-0","article-title":"A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K\/mTOR inhibitor GSK2126458 in patients with advanced solid tumors","volume":"34","author":"Bedard","year":"2016","journal-title":"Investig. New Drugs"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s10555-008-9126-y","article-title":"The tyrosine phosphatase Shp2 (PTPN11) in cancer","volume":"27","author":"Chan","year":"2008","journal-title":"Cancer Metastasis Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1182\/blood-2006-07-028829","article-title":"PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase","volume":"109","author":"Chan","year":"2007","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1038\/s41591-018-0024-8","article-title":"Mutant KRAS-driven cancers depend on PTPN11\/SHP2 phosphatase","volume":"24","author":"Ruess","year":"2018","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7773","DOI":"10.1021\/acs.jmedchem.6b00680","article-title":"Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor","volume":"59","author":"Chen","year":"2016","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1158\/2159-8290.CD-18-0444","article-title":"SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models","volume":"8","author":"Fedele","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e20201414","DOI":"10.1084\/jem.20201414","article-title":"SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling","volume":"218","author":"Fedele","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nature18621","article-title":"Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases","volume":"535","author":"Chen","year":"2016","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"100815","DOI":"10.1016\/j.xcrm.2022.100815","article-title":"Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer","volume":"3","author":"Frank","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Amante, R.J., Jehanno, C., De Silva, D., Coissieux, M.M., Ackerknecht, M., Romanet, V., Sethi, A., Hamelin, B., Preca, B.T., and Piscuoglio, S. (2023). PI3K inhibition circumvents resistance to SHP2 blockade in metastatic triple-negative breast cancer. J. Mammary Gland. Biol. Neoplasia, 28.","DOI":"10.1007\/s10911-023-09539-9"},{"key":"ref_49","first-page":"145","article-title":"Synergistic effects of SHP2 and PI3K pathway inhibitors in GAB2-overexpressing ovarian cancer","volume":"9","author":"Sun","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1002\/1878-0261.13377","article-title":"Rational combination of SHP2 and mTOR inhibition for the treatment of hepatocellular carcinoma","volume":"17","author":"Ramirez","year":"2023","journal-title":"Mol. Oncol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13058-022-01521-3","article-title":"Targeting SHP2 phosphatase in breast cancer overcomes RTK-mediated resistance to PI3K inhibitors","volume":"24","author":"Heynen","year":"2022","journal-title":"Breast Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1126\/science.1171362","article-title":"Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer","volume":"324","author":"Olive","year":"2009","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"85378","DOI":"10.18632\/oncotarget.19905","article-title":"Adiponectin receptor agonists inhibit leptin induced pSTAT3 and in vivo pancreatic tumor growth","volume":"8","author":"Messaggio","year":"2017","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/s41419-022-04572-8","article-title":"Synthetic adiponectin-receptor agonist, AdipoRon, induces glycolytic dependence in pancreatic cancer cells","volume":"13","author":"Manley","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.tips.2017.02.001","article-title":"A New View of Pathway-Driven Drug Resistance in Tumor Proliferation","volume":"38","author":"Nussinov","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1136\/gutjnl-2018-316822","article-title":"Combating pancreatic cancer with PI3K pathway inhibitors in the era of personalised medicine","volume":"68","author":"Conway","year":"2019","journal-title":"Gut"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1093\/jnci\/djs648","article-title":"PKB\/Akt-dependent regulation of cell motility","volume":"105","author":"Xue","year":"2013","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1136\/gutjnl-2014-307616","article-title":"A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras\/Mek\/Erk-induced hyperactive mTOR signalling","volume":"65","author":"Kong","year":"2016","journal-title":"Gut"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cell.2012.01.058","article-title":"Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism","volume":"149","author":"Ying","year":"2012","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.1101\/gad.1475506","article-title":"Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression","volume":"20","author":"Ijichi","year":"2006","journal-title":"Genes Dev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/s41422-019-0195-y","article-title":"Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma","volume":"29","author":"Peng","year":"2019","journal-title":"Cell Res."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Yang, K., Yang, T., Yu, J., Li, F., and Zhao, X. (2023). Integrated transcriptional analysis reveals macrophage heterogeneity and macrophage-tumor cell interactions in the progression of pancreatic ductal adenocarcinoma. BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10675-y"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3579","DOI":"10.1111\/cas.15495","article-title":"Tumor microenvironmental 15-PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer","volume":"113","author":"Bu","year":"2022","journal-title":"Cancer Sci."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Panebianco, C., Villani, A., Pisati, F., Orsenigo, F., Ulaszewska, M., Latiano, T.P., Potenza, A., Andolfo, A., Terracciano, F., and Tripodo, C. (2022). Butyrate, a postbiotic of intestinal bacteria, affects pancreatic cancer and gemcitabine response in in vitro and in vivo models. Biomed. Pharmacother., 151.","DOI":"10.1016\/j.biopha.2022.113163"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.1002\/1878-0261.13500","article-title":"Activation of the EGFR\/PI3K\/AKT pathway limits the efficacy of trametinib treatment in head and neck cancer","volume":"17","author":"Novoplansky","year":"2023","journal-title":"Mol. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7709","DOI":"10.1038\/sj.onc.1210580","article-title":"Functional inhibition of PI3K by the betaGBP molecule suppresses Ras-MAPK signalling to block cell proliferation","volume":"26","author":"Wells","year":"2007","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"21124","DOI":"10.1073\/pnas.1314124110","article-title":"PI3K regulates MEK\/ERK signaling in breast cancer via the Rac-GEF, P-Rex1","volume":"110","author":"Ebi","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1158\/2159-8290.CD-22-1066","article-title":"Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer","volume":"13","author":"Kemp","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jbior.2015.05.001","article-title":"Implication of PI3K\/Akt pathway in pancreatic cancer: When PI3K isoforms matter?","volume":"59","author":"Baer","year":"2015","journal-title":"Adv. Biol. 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