Cancer Res：他莫昔芬耐药性乳腺癌的治疗方法

美国俄亥俄州立大学综合癌症中心-阿瑟詹姆斯克肿瘤医院和Richard J. Solove研究所的研究人员已经发现乳腺癌细胞是如何抵抗他莫昔芬继续生长和增殖的。该研究也证实了一种新的试验性药物可靶向治疗他莫昔芬耐药性乳腺癌。

刺猬(Hhg)信号转导通路可以促进他莫昔芬关闭雌激素激活途径后乳腺癌细胞的生长。第二条信号转导通路PI3K/AKT也参与其中。Hhg信号通路的激活使他莫昔芬治疗无效，使肿瘤恢复增长和发展。

作为这项研究的一部分，研究人员分析了超过300例肿瘤样本，发现Hhg信号激活的肿瘤患者预后更差。最后，研究人员发现在动物模型中，实验性药物Vismodegib可阻止Hhg信号途径，抑制他莫昔芬耐药的人乳腺肿瘤的生长。该药物目前正在临床试验中测试对其它类型癌症的功效。

目前，化疗常用于治疗耐激素的乳腺癌，但这会带来显著副作用。本研究发现的抗肿瘤的靶向治疗药物可能是一个替代化疗手段的新的癌症治疗手段。这项研究发表在Cancer Research杂志上。第一作者Bhuvaneswari Ramaswamy博士说：我们的研究结果表明，我们可以针对他莫昔芬治疗失败的雌激素受体乳腺癌患者体内的这条信号途径来开展治疗。

分子和细胞生物化学研究助理教授Sarmila Majumder说：我们着重描述了促进他莫昔芬耐药性的产生以及能激活PI3K/AKT通路的Hedgehog信号通路。单独靶向Hedgehog信号通路或联合作用于Hedgehog信号通路和PI3K/AKT途径可能是治疗他莫昔芬耐药性乳腺癌的一种新的治疗选择。

doi:10.1158/0008-5472.CAN-12-1248
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Hedgehog signaling is a novel therapeutic target in tamoxifen resistant breast cancer aberrantly activated by PI3K/AKT pathway

Bhuvaneswari Ramaswamy, Yuanzhi Lu, Kun-yu Teng, Gerard Nuovo, Xiaobai Li, Charles L Shapiro, and Sarmila Majumder,*

Endocrine resistance is a major challenge in the management of estrogen-receptor (ER) positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of patients developing resistance to endocrine therapy warrants additional studies. Here we show that non-canonical Hedgehog (Hhg) signaling is an alternative growth promoting mechanism that is activated in tamoxifen-resistant tumors. Importantly, PI3K/AKT pathway plays a key role in regulating Hhg signaling by protecting key components of this pathway from proteasomal degradation. The levels of Hhg signaling molecules SMO, GLI1 and the targets were significantly elevated in tamoxifen-resistant MCF-7 cells and T47D cells. Serial passage of the resistant cells in mice resulted in aggressive tumors that metastasized to distant organs with concurrent increases in Hhg marker expression and epithelial mesenchymal transition. RNAi-mediated depletion of SMO or GLI1 in the resistant cells resulted in reduced proliferation, clonogenic survival and delayed G1-S transition. Notably, treatment of resistant cells with PI3K inhibitors decreased SMO and GLI1 protein levels and activity that was rescued upon blocking GSK3β and proteasomal degradation. Furthermore, treatment of tamoxifen resistant xenografts with anti-Hhg compound GDC-0449 blocked tumor growth in mice. Importantly, high GLI1 expression correlated inversely with disease-free and overall survival in a cohort of 315 breast cancer patients. In summary, our results describe a signaling event linking PI3K/AKT pathway with Hhg signaling that promotes tamoxifen resistance. Targeting Hhg pathway alone or in combination with PI3K/AKT pathway could therefore be a novel therapeutic option in treating endocrine resistant breast cancer.