Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer.
Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer.
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DOI：
10.1371/journal.pone.0171356
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Toyooka S
中科院分区：
文献类型：
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作者：
Takeda T;Yamamoto H;Kanzaki H;Suzawa K;Yoshioka T;Tomida S;Cui X;Murali R;Namba K;Sato H;Torigoe H;Watanabe M;Shien K;Soh J;Asano H;Tsukuda K;Kitamura Y;Miyoshi S;Sendo T;Toyooka S
在大约 15-23% 的乳腺癌中观察到人表皮生长因子受体 2 (HER2) 过度表达，这些癌症被归类为 HER2 阳性乳腺癌。曲妥珠单抗是 HER2 阳性乳腺癌的一线靶向治疗药物，可改善患者的总体生存率。然而，曲妥珠单抗的获得性耐药仍然是乳腺癌治疗中的一个关键问题。我们之前从曲妥珠单抗敏感的 HER2 扩增细胞系 BT-474 建立了曲妥珠单抗耐药乳腺癌细胞系（命名为 BT-474-R）。拉帕替尼也是一种针对 HER2 阳性乳腺癌的分子靶向药物，该乳腺癌对曲妥珠单抗产生了耐药性。对拉帕替尼的获得性耐药也是一个有待克服的问题。我们通过用拉帕替尼额外处理BT-474-R，建立了曲妥珠单抗/拉帕替尼双重耐药细胞系（命名为BT-474-RL2）。我们分析了曲妥珠单抗和拉帕替尼的耐药机制。此外，我们还分析了检测到的耐药机制对 HER2 阳性乳腺癌患者的影响。原癌基因酪氨酸蛋白激酶 Yes1 是 Src 家族成员之一，在 BT-474-R 和 BT-474-RL2 中被扩增、过表达和激活。通过 siRNA 沉默 Yes1 可诱导 BT-474-R 和 BT-474-RL2 恢复对曲妥珠单抗和拉帕替尼的敏感性。 Src 抑制剂达沙替尼对 Yes1 的药物抑制也能有效恢复两种耐药细胞系对曲妥珠单抗和拉帕替尼的敏感性。达沙替尼和曲妥珠单抗联合治疗可诱导 HER2 和 Akt 等信号分子下调。此外，联合治疗诱导 G1 期细胞周期停滞和细胞凋亡。与细胞系数据一致，Yes1 mRNA 的高表达与 HER2 阳性乳腺癌患者的预后较差相关。 Yes1 在 HER2 阳性乳腺癌中对曲妥珠单抗和拉帕替尼的获得性耐药中发挥重要作用。我们的数据表明，Yes1 的药理学抑制可能是克服曲妥珠单抗和拉帕替尼耐药性的有效策略。
Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15–23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumab-resistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered. We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients. Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer. Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.