Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth.
Combined blockade of Src kinase and epidermal growth factor receptor with gemcitabine overcomes STAT3-mediated resistance of inhibition of pancreatic tumor growth.
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SRC激酶和表皮生长因子受体与吉西他滨的结合阻断了STAT3介导的胰腺肿瘤生长抑制的耐药性。
DOI：
10.1158/1078-0432.ccr-10-1670
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Merchant NB
中科院分区：
文献类型：
--
作者：
Nagaraj NS;Washington MK;Merchant NB
我们之前建立了Src抑制作为胰腺癌新治疗靶点的机制原理，并表明活化的STAT3是Src抑制抗性的生物标志物。本研究的目的是通过靶向Src激酶和表皮生长因子受体（EGFR）来翻译目前对互补激活酪氨酸激酶信号通路的理解。测定达沙替尼（一种Src激酶抑制剂）、厄洛替尼（一种EGFR酪氨酸激酶抑制剂）和吉西他滨的IC50值，并鉴定敏感和耐药胰腺癌细胞系。研究了这些药物对胰腺癌多种信号通路和致瘤性的体外和体内影响。达沙替尼、厄洛替尼和吉西他滨的组合导致对敏感性和抗性胰腺癌细胞的细胞迁移和侵袭的协同抑制，以及对多种信号传导途径的协同抑制，包括FAK、AKT、ERK、JNK、MAPK和STAT3，其浓度作为单独药剂或作为药剂的双重组合无效。试剂的三重组合在体内抑制敏感性和抗性胰腺癌细胞的异种移植物的生长方面也是最有效的，而不增加毒性。此外，Src和EGFR与吉西他滨的组合抑制在体外和体内抑制组成型活化的STAT3。这些结果提供了证据表明，除了细胞毒性化疗外，联合靶向生物治疗可以克服治疗耐药性。此类治疗策略可用于基于鉴定的对靶向单一疗法的抗性的生物标志物来定制治疗。
We previously established a mechanistic rationale for Src inhibition as a novel therapeutic target in pancreatic cancer and have shown that activated STAT3 is a biomarker of resistance to Src inhibition. The purpose of this study was to translate the current understanding of complementary activated tyrosine kinase signaling pathways by targeting Src kinase and epidermal growth factor receptor (EGFR). IC50 values for dasatinib, a Src kinase inhibitor, erlotinib, an EGFR tyrosine kinase inhibitor and gemcitabine were determined and sensitive and resistant pancreatic cancer cell lines were identified. The in vitro and in vivo effects of these agents on multiple signaling pathways and tumorigenicity in pancreatic cancer were investigated. The combination of dasatinib, erlotinib and gemcitabine resulted in cooperative inhibition of cell migration and invasion of both sensitive and resistant pancreatic cancer cells as well as cooperative inhibition of multiple signaling pathways including FAK, AKT, ERK, JNK, MAPK and STAT3 at concentrations that were ineffective as individual agents or as double combinations of agents. The triple combination of agents was also most effective at inhibiting the growth of xenografts of both sensitive and resistant pancreatic cancer cells in vivo without increasing toxicity. Furthermore, combined inhibition of Src and EGFR with gemcitabine inhibited constitutively activated STAT3 in vitro and in vivo. These results provide evidence that combined targeted biological therapy in addition to cytotoxic chemotherapy can overcome treatment resistance. Such treatment strategies may be used to tailor therapy based on identified biomarkers of resistance to targeted monotherapy.