Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer.
Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer.
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DOI：
10.1158/0008-5472.can-12-4047
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发表时间：
2013-06-01
期刊：
影响因子：
11.2
通讯作者：
Jimeno A
中科院分区：
文献类型：
--
作者：
Keysar SB;Le PN;Anderson RT;Morton JJ;Bowles DW;Paylor JJ;Vogler BW;Thorburn J;Fernandez P;Glogowska MJ;Takimoto SM;Sehrt DB;Gan GN;Eagles-Soukup JR;Serracino H;Hirsch FR;Lucia MS;Thorburn A;Song JI;Wang XJ;Jimeno A
表皮生长因子受体（EGFR）导向的单克隆抗体西妥昔单抗是唯一被批准用于治疗头颈部鳞状细胞癌（HNSCC）的靶向治疗，但仅对少数患者有效。上皮-间质转化（EMT）已被认为是多种癌症的耐药机制，EGFR和Hedgehog通路（HhP）与此过程相关，但在HNSCC中尚未确定这两种通路之间的相互作用。在这里，我们表明，随着时间的推移，对EGFR抑制天然敏感的HNSCC细胞随着EGFR抑制剂长期暴露后变得耐药，HhP转录因子GLI 1的表达增加。这与波形蛋白表达的增加密切相关。相反，HhP负调控HNSCC细胞中的EGFR依赖性、EMT样状态，并且HhP信号传导的药理学或遗传学抑制将细胞进一步推向EGFR依赖性表型，增加ZEB 1和Vim的表达。西妥昔单抗的体内治疗导致六分之四的HNSCC患者来源的异种移植物中的肿瘤缩小;然而，它们最终重新生长。西妥昔单抗联合HhP抑制剂IPI-926消除了两例肿瘤，并显著延迟了另外两例的再生长。EMT基因TWIST和ZEB 2的表达在敏感的异种移植物中增加，表明可能存在耐药间充质细胞群。总之，我们报告EGFR依赖性HNSCC细胞可以经历EGFR依赖性和非依赖性EMT，HhP信号是这两个过程中的调节剂。西妥昔单抗加IPI-926迫使肿瘤细胞进入EGFR依赖性状态，延迟或完全阻断肿瘤复发。
The epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab is the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC), but is only effective in a minority of patients. Epithelial-to-mesenchymal transition (EMT) has been implicated as a drug resistance mechanism in multiple cancers, and the EGFR and Hedgehog pathways (HhP) are relevant to this process, but the interplay between the two pathways has not been defined in HNSCC. Here we show that HNSCC cells that were naturally sensitive to EGFR inhibition over time developed increased expression of the HhP transcription factor GLI1 as they became resistant after long-term EGFR inhibitor exposure. This robustly correlated with an increase in Vimentin expression. Conversely, the HhP negatively regulated an EGFR-dependent, EMT-like state in HNSCC cells, and pharmacological or genetic inhibition of HhP signaling pushed cells further into an EGFR-dependent phenotype, increasing expression of ZEB1 and VIM. In vivo treatment with cetuximab resulted in tumor shrinkage in four out of six HNSCC patient-derived xenografts; however they eventually re-grew. Cetuximab in combination with the HhP inhibitor IPI-926 eliminated tumors in two cases and significantly delayed re-growth in the other two cases. Expression of EMT genes TWIST and ZEB2 was increased in sensitive xenografts suggesting a possible resistant mesenchymal population. In summary, we report that EGFR-dependent HNSCC cells can undergo both EGFR-dependent and -independent EMT and HhP signaling is a regulator in both processes. Cetuximab plus IPI-926 forces tumor cells into an EGFR-dependent state delaying or completely blocking tumor recurrence.