Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma.
Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma.
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DOI：
10.1016/j.oraloncology.2016.05.007
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发表时间：
2016-08
期刊：
影响因子：
4.8
通讯作者：
Kirma NB
中科院分区：
文献类型：
--
作者：
Gonzales CB;De La Chapa JJ;Saikumar P;Singha PK;Dybdal-Hargreaves NF;Chavez J;Horning AM;Parra J;Kirma NB
鳞状细胞癌（SCC）占所有头颈部癌症的90%，由于疾病晚期，对传统疗法来说是屈光性的，因此生存率很低。表皮生长因子受体（EGFR）在超过80%的头颈部鳞状细胞癌（HNSCC）中过表达。然而，EGFR靶向治疗在临床试验中几乎没有疗效。本研究探讨了共同靶向EGFR和启动子低甲基化的间变性淋巴瘤激酶（ALK）在晚期口腔鳞状细胞癌（OSCC）中的疗效。我们观察到晚期人类OSCC肿瘤和侵袭性OSCC细胞系中ALK活性增加。我们还发现，虽然单独抑制ALK对细胞增殖的影响不大，但联合靶向ALK和EGFR可显著降低体外OSCC细胞的增殖。进一步分析显示，联合治疗hsc3来源的异种移植物的显著疗效，14天内肿瘤体积减少30% （p < 0.001）。Western blot分析显示，共靶向ALK和EGFR可显著降低HSC3细胞中EGFR磷酸化（Y1148），但对Cal27细胞无显著影响。Western blot分析也证实了ALK和EGFR的下游信号相互作用，其中单独的EGFR和ALK抑制剂减弱了AKT的活性，而共同靶向ALK和EGFR则完全消除了AKT的活性。未观察到对ERK1/2激活的影响。在HSC3细胞中，单独抑制ALK可显著诱导STAT3活性，而在Cal27细胞中，STAT3活性的诱导程度较低。综上所述，这些数据表明，在ALK表达增加的易感肿瘤中，ALK抑制剂增强了EGFR抑制剂的抗肿瘤活性，这很可能是通过消除AKT激活来实现的。
Squamous cell carcinoma (SCC) comprises 90% of all head and neck cancers and has a poor survival rate due to late-stage disease that is refractive to traditional therapies. Epidermal growth factor receptor (EGFR) is over-expressed in greater than 80% of head and neck SCC (HNSCC). However, EGFR targeted therapies yielded little to no efficacy in clinical trials. This study investigated the efficacy of co-targeting EGFR and the anaplastic lymphoma kinase (ALK) whose promoter is hypomethylated in late-stage oral SCC (OSCC). We observed increased ALK activity in late-stage human OSCC tumors and invasive OSCC cell lines. We also found that while ALK inhibition alone had little effect on proliferation, co-targeting ALK and EGFR significantly reduced OSCC cell proliferation in vitro. Further analysis showed significant efficacy of combined treatment in HSC3-derived xenografts resulting in a 30% decrease in tumor volumes by 14 days (p < 0.001). Western blot analysis showed that co-targeting ALK and EGFR significantly reduced EGFR phosphorylation (Y1148) in HSC3 cells but not Cal27 cells. ALK and EGFR downstream signaling interactions are also demonstrated by Western blot analysis in which lone EGFR and ALK inhibitors attenuated AKT activity whereas co-targeting ALK and EGFR completely abolished AKT activation. No effects were observed on ERK1/2 activation. STAT3 activity was significantly induced by lone ALK inhibition in HSC3 cells and to a lower extent in Cal27 cells. Together, these data illustrate that ALK inhibitors enhance anti-tumor activity of EGFR inhibitors in susceptible tumors that display increased ALK expression, most likely through abolition of AKT activation.