PMID- 30154150 OWN - NLM STAT- MEDLINE DCOM- 20191007 LR - 20220408 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 78 IP - 21 DP - 2018 Nov 1 TI - Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer. PG - 6235-6246 LID - 10.1158/0008-5472.CAN-18-0634 [doi] AB - Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1a(cre/+); LSL-Kras(G12D/+) ; and Tgfbr2(flox/flox) (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL-Kras(G12D/+);Trp53(R172H/+);Pdx1(Cre/+) (KPC), and PKT mice. MEKi/STAT3i-treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in an immediate activation of STAT3, whereas STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to individual MEKi or STAT3i. This combined inhibition attenuated tumor growth in PDX and increased survival of PKT mice while reducing serum AREG levels. Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44(+) and CD133(+) CSCs. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, whereas TACE-AREG-EGFR-dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition. Combined MEKi/STAT3i overcomes these resistances and provides a novel therapeutic strategy to target the RAS and STAT3 pathway in PDAC.Significance: This report describes an inverse correlation between MEK and STAT3 signaling as key mechanisms of resistance in PDAC and shows that combined inhibition of MEK and STAT3 overcomes this resistance and provides an improved therapeutic strategy to target the RAS pathway in PDAC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg Cancer Res; 78(21); 6235-46. (c)2018 AACR. CI - (c)2018 American Association for Cancer Research. FAU - Nagathihalli, Nagaraj S AU - Nagathihalli NS AD - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. AD - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. FAU - Castellanos, Jason A AU - Castellanos JA AD - Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Lamichhane, Purushottam AU - Lamichhane P AD - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. FAU - Messaggio, Fanuel AU - Messaggio F AD - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. FAU - Shi, Chanjuan AU - Shi C AD - Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee. FAU - Dai, Xizi AU - Dai X AD - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. FAU - Rai, Priyamvada AU - Rai P AD - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. AD - Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida. FAU - Chen, Xi AU - Chen X AD - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. AD - Department of Public Health, University of Miami Miller School of Medicine, Miami, Florida. FAU - VanSaun, Michael N AU - VanSaun MN AD - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. AD - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. FAU - Merchant, Nipun B AU - Merchant NB AD - Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida. nmerchant@med.miami.edu. AD - Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida. LA - eng GR - R01 CA161976/CA/NCI NIH HHS/United States GR - R01 CA175086/CA/NCI NIH HHS/United States GR - R21 CA209536/CA/NCI NIH HHS/United States GR - T32 CA211034/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180828 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (KRAS protein, human) RN - 0 (Ligands) RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) RN - EC 2.7.12.2 (MAP Kinase Kinase 1) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Amphiregulin/metabolism MH - Animals MH - Carcinoma, Pancreatic Ductal/metabolism/pathology MH - Cell Line, Tumor MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Ligands MH - MAP Kinase Kinase 1/*metabolism MH - Mice MH - Mice, Nude MH - Mutation MH - Neoplasm Transplantation MH - Pancreatic Neoplasms/*drug therapy/*metabolism MH - Phosphorylation MH - Proto-Oncogene Proteins p21(ras)/metabolism MH - STAT3 Transcription Factor/*metabolism MH - Signal Transduction MH - Tissue Array Analysis MH - Tumor Microenvironment MH - ras Proteins/*metabolism PMC - PMC6878978 MID - NIHMS1505398 COIS- Conflict of Interest: The authors declare they have no conflict of interest. EDAT- 2018/08/30 06:00 MHDA- 2019/10/08 06:00 PMCR- 2019/11/26 CRDT- 2018/08/30 06:00 PHST- 2018/02/27 00:00 [received] PHST- 2018/07/05 00:00 [revised] PHST- 2018/08/22 00:00 [accepted] PHST- 2018/08/30 06:00 [pubmed] PHST- 2019/10/08 06:00 [medline] PHST- 2018/08/30 06:00 [entrez] PHST- 2019/11/26 00:00 [pmc-release] AID - 0008-5472.CAN-18-0634 [pii] AID - 10.1158/0008-5472.CAN-18-0634 [doi] PST - ppublish SO - Cancer Res. 2018 Nov 1;78(21):6235-6246. doi: 10.1158/0008-5472.CAN-18-0634. Epub 2018 Aug 28.