{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T16:19:23Z","timestamp":1789661963323,"version":"4.0.1"},"reference-count":46,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T00:00:00Z","timestamp":1579478400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"David C. Koch Regional Therapy Cancer Center"},{"name":"Pseudomyxoma Peritonei Philanthropic Research Fund"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2020,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Molecular\u2010targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK\u2010PI3K drug therapy against KRAS mutated mucin 2 (MUC2)\u2010secreting LS174T cells and patient\u2010derived ex vivo and in vivo models of KRAS mutated mucinous colon\/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co\u2010therapy. Co\u2010treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)\u2010induced synergistic cytotoxicity and intrinsic mitochondrial\u2010mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)\u2010associated proteins (GRP78\/BiP, ATF4, and CHOP). However, CHOP knock\u2010down assays demonstrated that mitochondrial\u2010mediated apoptosis in LS174T cells was not ERS\u2010dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post\u2010translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient\u2010derived xenograft models derived from mucinous colon\/appendix cancer. These promising preclinical data support a role for dual MEK\u2010PI3K inhibitor therapy in mucinous colon\/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co\u2010treatment based on their unique phenotypic and genotypic characteristics.<\/jats:p>","DOI":"10.1002\/cam4.2847","type":"journal-article","created":{"date-parts":[[2020,1,21]],"date-time":"2020-01-21T01:34:08Z","timestamp":1579570448000},"page":"1753-1767","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Rational application of targeted therapeutics in mucinous colon\/appendix cancers with positive predictive factors"],"prefix":"10.1002","volume":"9","author":[{"given":"Ashokkumar","family":"Dilly","sequence":"first","affiliation":[{"name":"Department of Surgery University of Pittsburgh Medical Center Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendon D.","family":"Honick","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Pittsburgh Medical Center Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong J.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Pittsburgh Medical Center Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Pittsburgh Medical Center Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9159-9594","authenticated-orcid":false,"given":"Haroon A.","family":"Choudry","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Pittsburgh Medical Center Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,1,20]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/1570163812666150602144310"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2013.11.004"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1235122"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28864"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.3641"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/1758834015571111"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-12-612"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0349"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/gm559"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0087966"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/cjp2.1"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2014.225565"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.47"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.542"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29245"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdw314"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.22147"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2014.04.018"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2011.112"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-4-8"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00063.2010"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.6064\/2012\/857516"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2014.01.009"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-2047"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2011.12.006"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.22455"},{"issue":"19","key":"e_1_2_7_29_1","first-page":"e11","article-title":"Targeting hypoxia\u2010mediated mucin 2 production as a therapeutic strategy for mucinous tumors","volume":"169","author":"Dilly AK","year":"2016","journal-title":"Transl Res"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2015.03.004"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.3791\/52483-v"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004030050436"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.225"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.4103\/0976-500X.119726"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2017.174060"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0179510"},{"key":"e_1_2_7_37_1","doi-asserted-by":"crossref","DOI":"10.1200\/jco.2012.30.15_suppl.2566","article-title":"A first\u2010in\u2010human phase 1b study to evaluate the MEK inhibitor GDC\u20100973 combined with the pan\u2010PI3K inhibitor GDC\u20100941, in patients with advanced solid tumors","volume":"30","author":"LoRusso P","year":"2012","journal-title":"J Clin Oncol."},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.32.15_suppl.2588"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1814"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2014.32.15_suppl.9051"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.12055"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clcc.2018.07.005"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.21701"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28347"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2761"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jso.23146"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.2741\/Seuning"}],"container-title":["Cancer Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcam4.2847","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.2847","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cam4.2847","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cam4.2847","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,10]],"date-time":"2024-10-10T14:46:16Z","timestamp":1728571576000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/cam4.2847"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,20]]},"references-count":46,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,3]]}},"alternative-id":["10.1002\/cam4.2847"],"URL":"https:\/\/doi.org\/10.1002\/cam4.2847","archive":["Portico"],"relation":{},"ISSN":["2045-7634","2045-7634"],"issn-type":[{"value":"2045-7634","type":"print"},{"value":"2045-7634","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,20]]},"assertion":[{"value":"2019-11-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-12-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-01-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}