Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida.
Cancer Res. 2018 Nov 1;78(21):6235-6246. doi: 10.1158/0008-5472.CAN-18-0634. Epub 2018 Aug 28.
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 .
胰腺导管腺癌 (PDAC) 治疗耐药的主要原因包括 突变、阻止药物输送到肿瘤的密集细胞外基质和冗余信号通路的激活。我们之前已经确定了针对 STAT3 信号靶向以克服 PDAC 治疗耐药性的机制原理。在这项研究中，我们研究了 PDAC 中 STAT3 和 RAS 通路抑制的异质反应的分子机制。在 ；和 （PKT）小鼠和患者来源的异种移植物（PDX）中建立了 JAK/STAT3 抑制（STAT3i）或 MEK 抑制（MEKi）的作用。从患有 PDAC 的人类患者、LSL-（KPC）和 PKT 小鼠的血清中测定了 Amphiregulin (AREG) 水平。分析了 MEKi/STAT3i 处理的肿瘤的胰腺完整性和癌症干细胞 (CSC) 的存在。我们观察到 ERK 和 STAT3 磷酸化之间存在反比关系。MEKi 导致 STAT3 的立即激活，而 STAT3i 导致 TACE 诱导的、AREG 依赖性的 EGFR 和 ERK 激活。MEKi/STAT3i 的联合抑制持续阻断 ERK、EGFR 和 STAT3 信号，克服了对单独 MEKi 或 STAT3i 的耐药性。这种联合抑制抑制在 PDX 中肿瘤生长并增加 PKT 小鼠的存活率，同时降低血清 AREG 水平。此外，MEKi/STAT3i 通过耗尽肿瘤纤维化、维持胰腺完整性和下调 CD44 和 CD133 CSCs 改变 PDAC 肿瘤微环境。这些结果表明，对 MEKi 的耐药性是通过 STAT3 的激活介导的，而 TACE-AREG-EGFR 依赖性的 RAS 通路信号的激活赋予了对 STAT3 抑制的耐药性。MEKi/STAT3i 的联合抑制克服了这些耐药性，并为靶向 PDAC 中的 RAS 和 STAT3 通路提供了一种新的治疗策略。本报告描述了 MEK 和 STAT3 信号之间的反比关系作为 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性，并为靶向 PDAC 中的 RAS 通路提供了一种改进的治疗策略。http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg.
