Dual Targeting of ERBB2/ERBB3 for the Treatment of SLC3A2-NRG1-Mediated Lung Cancer
Dual Targeting of ERBB2/ERBB3 for the Treatment of SLC3A2-NRG1-Mediated Lung Cancer
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DOI：
10.1158/1535-7163.mct-17-1178
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发表时间：
2018-09-01
影响因子：
5.7
通讯作者：
Han, Ji-Youn
中科院分区：
文献类型：
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作者：
Shin, Dong Hoon;Jo, Jeong Yeon;Han, Ji-Youn
我们在非小细胞肺癌（NSCLC）中鉴定了SLC 3A 2-NRG 1融合基因，并为SLC 3A 2-NRG 1融合阳性癌症患者建立了有效的治疗方法。SLC 3A 2-NRG 1融合产物由SLC 3A 2跨膜结构域和神经调节蛋白1（NRG 1）蛋白的EGF样结构域组成。NRG 1家族被归类为ERBB家族的配体。我们通过配体和受体结合试验鉴定了ERBB家族中的ERBB 3和ERBB 4作为SLC 3A 2-NRG 1融合蛋白的结合伴侣。我们证实了SLC 3A 2-NRG 1增加了ERBB 3与ERBB 2的异源复合物的形成。SLC 3A 2-NRG 1激活ERBB 2-ERBB 3异源复合物通过PI 3 K-AKT和MAP激酶增加集落形成和肿瘤生长。ERBB 2和ERBB 3、帕妥珠单抗、鲁妥珠单抗和阿法替尼的特异性siRNA均降低了ERBB 2-ERBB 3杂复合物形成、每种蛋白的磷酸化及其下游信号传导。此外，帕妥珠单抗、鲁姆妥珠单抗或阿法替尼单药治疗可降低肿瘤体积和重量，而与各单药治疗相比，这些药物和紫杉醇联合治疗可增加叶片型半胱天冬酶3、PARP和TUNEL阳性细胞的生成。因此，SLC 3A 2-NRG 1融合基因通过促进ERBB 2-ERBB 3异源复合物的产生、其磷酸化和PI 3 K/ERK/mTOR信号通路的激活，在肺癌细胞增殖和肿瘤生长中起重要作用。单独抑制ERBB 2或ERBB 3并不能完全关闭ERBB 2和ERBB 3的下游信号传导;然而，ERBB 2和ERBB 3的抑制阻断了SLC 3A 2-NRG 1融合激活的下游信号传导。ERBB 2和ERBB 3可能是治疗SLC 3A 2-NRG 1阳性肿瘤的有希望的靶点。(C)2018年AACR。
We characterized the SLC3A2-NRG1 fusion gene in non-small cell lung cancer (NSCLC) and established an effective therapy for patients with SLC3A2-NRG1 fusion-positive cancer. The SLC3A2-NRG1 fusion product was composed of the SLC3A2 transmembrane domain and the EGF-like domain of the neuregulin 1 (NRG1) protein. The NRG1 family is classified as a ligand of the ERBB family. We identified ERBB3 and ERBB4 in the ERBB family as binding partners of the SLC3A2-NRG1 fusion protein via ligand and receptor binding assays. We confirmed that SLC3A2-NRG1 increased formation of a heterocomplex of ERBB3 with ERBB2. Activation of the ERBB2-ERBB3 heterocomplex by SLC3A2-NRG1 increased colony formation and tumor growth through PI3K-AKT and MAP kinase. The specific siRNAs for ERBB2 and ERBB3, pertuzumab, lumretuzumab, and afatinib all decreased ERBB2-ERBB3 heterocomplex formation, phosphorylation of each protein, and their downstream signaling. In addition, single treatment with pertuzumab, lumretuzumab, or afatinib decreased tumor volume and weight, whereas combination treatment with these drugs and taxol enhanced generation of leaved caspase 3, PARP, and TUNEL-positive cells compared with each single treatment. Thus, the SLC3A2-NRG1 fusion gene plays an important role in lung cancer cell proliferation and tumor growth by promoting generation of the ERBB2-ERBB3 heterocomplex, its phosphorylation, and activation of the PI3K/ERK/mTOR signaling pathway. Inhibition of either ERBB2 or ERBB3 alone did not completely shut down downstream signaling of ERBB2 and ERBB3; however, inhibition of both ERBB2 and ERBB3 blocked downstream signaling activated by SLC3A2-NRG1 fusion. ERBB2 and ERBB3 might be promising targets for treatment of SLC3A2-NRG1-positive tumors. (C) 2018 AACR.