Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer

Abstract

Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include 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 ; and (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL- (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. 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. http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg .

Hyperglycemia enhances pancreatic cancer progression accompanied by elevations in phosphorylated STAT3 and MYC levels

“…STAT3 and ERK showed an inverse relation under hyperglycemic conditions and STAT3 inhibition. An inverse relation between pERK and pSTAT3 in Kras-mutant pancreatic cancer cells has been reported recently, supporting our data [31]. Upon treatment with the STAT3 inhibitor STATTIC, low-glucose-maintained cells showed a stronger tendency toward enhanced ERK phosphorylation than did high-glucose-maintained cells.…”

MEK inhibition activates STAT signaling to increase breast cancer immunogenicity via MHC-I expression

“…Next, we tested whether inhibition of ErbB family receptors would affect MHC-I and PD-L1 expression. Basal MHC-I and PD-L1 expression levels were unaffected by erlotinib or lapatinib treatment Previous reports have suggested a connection between MEK-ERK and STAT signaling in pancreatic cancer patient-derived xenograft models, but whether the relationship is conserved in breast cancers is unknown [24] . We initially tested a panel of human breast cancer cell lines for MEKi-induced STAT activation [ Figure 7A; Supplemental Figure 5].…”

Markers of pancreatic cancer stem cells and their clinical and therapeutic implications

“…Its activation could be performed by a downstream signaling pathway initiated by one of the extracellular signal-regulated kinases (ERKs), mainly by ERK1 or ERK2 [35]. In CSCs of PC ERKs are inducted by MAPK/ERK pathway triggered through the TrkA receptor in response to auto-or paracrine secreted Nerve growth factor (NGF) [36][37][38][39]. On the other hand P5 appears to be a target for heat shock proteins such as HIF-1α and HIF-2α [35].Their expression increases during carcinogenesis in pancreatic tissue due to oxygen deficiency in the PC region, leading to increased CD133 transcription [40][41][42].…”

“…Other studies showed that Wnt/β-catenin signaling has been closely associated with regulating PC development and has promoted the self-renewal of CD133+ cancer cells [43][44][45]. Moreover, a study by Nagathihalli et al showed that inhibition of Janus kinases (JAK) or Signal Transducer and Activator of Transcription protein 3 (STAT3) cause downregulation of CD133 + [39]. Recent studies have revealed significantly lower expression of CD133 in normal pancreatic tissue (in under 0.01% of cancer cells) in regards to PC [46] [38].…”

“…Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. [33], [35]- [39],…”