Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer.
Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer.
复制标题
DOI：
10.1158/0008-5472.can-18-0634
复制
发表时间：
2018-11-01
期刊：
影响因子：
11.2
通讯作者：
Merchant NB
中科院分区：
文献类型：
--
作者：
Nagathihalli NS;Castellanos JA;Lamichhane P;Messaggio F;Shi C;Dai X;Rai P;Chen X;VanSaun MN;Merchant NB
胰腺癌治疗耐药（PDAC）的主要因素包括Kras突变，一种阻止药物传递到肿瘤的致密的间质，以及冗余信号通路的激活。我们之前已经确定了靶向STAT3信号以克服PDAC治疗耐药的机制原理。在这项研究中，我们研究了PDAC对STAT3和RAS通路抑制的异质性反应的分子机制。JAK/STAT3抑制（STAT3i）或MEK抑制（MEKi）在Ptf1acre/+， LSL-KrasG12D/+；Tgfbr2flox/flox （PKT）小鼠和患者来源的异种移植物（PDX）。测定人PDAC患者血清中双调节蛋白（AREG）水平，LSL-KrasG12D/+, Trp53R172H/+；Pdx1Cre/+ (KPC)和PKT小鼠。分析MEKi/ stat3i治疗的肿瘤胰腺的完整性和癌症干细胞（CSC）的存在。我们观察到ERK和STAT3磷酸化之间呈负相关。MEKi导致STAT3立即激活，而STAT3i导致tace诱导的、areg依赖性的EGFR和ERK激活。联合MEKi/STAT3i持续阻断ERK、EGFR和STAT3信号，克服对单个MEKi或STAT3i的耐药性。这种联合抑制抑制了PDX的肿瘤生长，提高了PKT小鼠的存活率，同时降低了血清AREG水平。此外，MEKi/STAT3i通过消耗肿瘤纤维化、维持胰腺完整性和下调CD44+和CD133+ CSC来改变PDAC肿瘤微环境。这些结果表明，对MEKi的抗性是通过STAT3的激活介导的，而依赖于tace - areg - egfr的RAS通路信号的激活则赋予了对STAT3抑制的抗性。MEKi/STAT3i联合治疗克服了这些耐药性，并提供了一种针对PDAC中RAS和STAT3通路的新治疗策略。本报告描述了MEK和STAT3信号之间的负相关关系是PDAC耐药的关键机制，并表明MEK和STAT3的联合抑制克服了这种耐药，并提供了一种针对PDAC中RAS通路的改进的治疗策略。
Major contributors to therapeutic resistance in pancreatic cancer (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 Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human PDAC patients, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (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 immediate activation of STAT3, while 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+ CSC. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, while 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.