University of Colorado Cancer Center, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA.
Neoplasia. 2012 Aug;14(8):690-701. doi: 10.1593/neo.111810.
The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer.
Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated.
Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression.
SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.
目前仍不清楚哪些因素会阻碍支持胰腺癌临床开发的临床前研究发现转化为临床实践。本研究以基质细胞衍生因子 1α（SDF-1α）-CXCR4 信号转导为例，探讨其作为一种能够促进胰腺癌细胞对 mTOR 靶向治疗产生耐药性的代表性微环境因素。
本研究使用原代胰腺外植体异种移植和体外实验来进行 SDF-1α-CXCR4 调节 mTOR 通路的药效学分析。在西罗莫司耐药和敏感的异种移植模型中评估 CXCR4、EGFR 和 mTOR 药理学抑制的联合作用。评估 mTOR 通路效应物 cyclin D1、c-Myc 和 VEGF 的肿瘤内基因和蛋白表达。
原代模型中，肿瘤内 SDF-1α 基因表达与西罗莫司耐药相关。SDF-1α 刺激胰腺细胞后，西罗莫司暴露时会导致 CXCR4 介导的 PI3-激酶依赖性 S6-RP 磷酸化（pS6-RP）。AMD3465（CXCR4 小分子抑制剂）与西罗莫司联合治疗可有效抑制肿瘤生长，克服西罗莫司耐药性。相比之下，SDF-1α 暴露会诱导西罗莫司敏感的外植体产生西罗莫司耐药表型。AMD3465 抑制 CXCR4 介导的肿瘤内 S6-RP 磷酸化和 cyclin D 和 c-Myc 基因表达。随后，CXCR4 促进了肿瘤内 EGFR 表达与西罗莫司耐药相关。AMD3465、西罗莫司和厄洛替尼治疗可抑制肿瘤生长，克服外植体模型中的西罗莫司耐药性。最后，SDF-1α-CXCR4 信号转导增加了肿瘤内 VEGF 基因和蛋白的表达。
SDF-1α-CXCR4 信号转导是一种微环境因素，它可以通过多种机制（如招募 EGFR 信号和血管生成）来维持 mTOR 通路的保真度，从而促进胰腺癌细胞对 mTOR 靶向治疗产生耐药性。
