Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.
Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment.
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Pan-erbB 抑制可增强 BRAF 抑制剂对黑色素瘤的治疗作用。
DOI：
10.1097/cmr.0000000000000060
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发表时间：
2014
影响因子：
2.2
通讯作者：
Stabile,LauraP
中科院分区：
文献类型：
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作者：
Ng,Yuen-Keng;Lee,Jia-Ying;Supko,KathrynM;Khan,Ayesha;Torres,SalinaM;Berwick,Marianne;Ho,Jonhan;Kirkwood,JohnM;Siegfried,JillM;Stabile,LauraP
BRAF抑制剂维莫拉非尼目前用于治疗BRAF V600E突变黑色素瘤患者。然而，对维莫拉非尼的反应一般是部分的，持续时间相对较短。最近的证据表明，表皮生长因子受体(EGFR)/erbB信号通路的激活可能与黑色素瘤患者BRAF抑制剂耐药的发生有关。在这项研究中，我们鉴定了黑色素瘤细胞株中的erbB受体和配体家族，并研究了同时靶向BRAF和erbB是否能增强BRAF突变黑色素瘤的抗肿瘤活性。在BRAF野生型和突变型黑色素瘤细胞中都表达了不同水平的erbB2、erbB3和截短型ERBB4，野生型和突变型之间没有显著差异。EGFR很少表达。神经调节蛋白3和神经调节蛋白4是黑色素瘤细胞释放的主要erbB配体。在BRAF野生型和突变型黑色素瘤细胞中，不可逆酪氨酸激酶抑制剂canertinib靶向的多erb B比单、双erb B靶向抑制剂吉非替尼、厄洛替尼和拉帕替尼具有更有效的生长抑制作用。在突变型和野生型细胞系中，Canertinib同时抑制EGF诱导的和NeuRegin 1诱导的erbB下游信号。然而，Canertinib仅在突变细胞中诱导细胞凋亡和亚G1期停滞。Canertinib可显著增强维莫拉非尼对BRAF突变型黑色素瘤细胞株的抗增殖作用，而联合用药对野生型黑色素瘤细胞株的抑制作用很小或没有增强作用。针对BRAF的联合抑制策略和多个erb B家族的激酶对治疗BRAF V600E突变的黑色素瘤具有潜在的益处。野生型BRAF黑色素瘤也可能受益于多种erbB激酶抑制剂。
The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.