Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells.
Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells.
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PI3K/Akt/mTOR途径抑制剂联合治疗克服了pik3ca突变her2阳性乳腺癌细胞抗her2治疗的耐药。
DOI：
10.1038/s41598-020-78646-y
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发表时间：
2020-12-10
影响因子：
4.6
通讯作者：
Mukohara T
中科院分区：
文献类型：
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作者：
Fujimoto Y;Morita TY;Ohashi A;Haeno H;Hakozaki Y;Fujii M;Kashima Y;Kobayashi SS;Mukohara T
在15-20%的乳腺癌（HER 2+乳腺癌）中观察到人表皮生长因子受体2（HER 2）扩增和/或过表达，抗HER 2治疗显著改善了HER 2+乳腺癌患者的预后。抗HER 2疗法的一种耐药机制是磷脂酰肌醇3-激酶（PI 3 K）途径的组成性激活。在具有或不具有PIK 3CA突变的HER 2+乳腺癌细胞系中使用AKT和HER 2的小分子抑制剂进行联合治疗，所述PIK 3CA突变导致PI 3 K途径的组成性激活。PIK 3CA突变在乳腺癌细胞系对单药抗HER 2治疗的耐药性中起重要作用。HER 2抑制剂和AKT抑制剂以及其他PI 3 K通路抑制剂的联合治疗可以克服PIK 3CA突变型HER 2+乳腺癌细胞系中与单药抗HER 2治疗相关的治疗限制。此外，治疗后磷酸化4 E结合蛋白1（p4 EBP 1）的表达与联合治疗的抗增殖活性相关，表明p4 EBP 1可能具有作为这些联合治疗的预后和/或疗效相关生物标志物的潜力。这些发现强调了使用联合治疗克服与HER 2+乳腺癌患者中单药抗HER 2治疗相关的局限性的潜在临床策略。
Amplification and/or overexpression of human epidermal growth factor receptor 2 (HER2) are observed in 15–20% of breast cancers (HER2+ breast cancers), and anti-HER2 therapies have significantly improved prognosis of patients with HER2+ breast cancer. One resistance mechanism to anti-HER2 therapies is constitutive activation of the phosphoinositide 3-kinase (PI3K) pathway. Combination therapy with small-molecule inhibitors of AKT and HER2 was conducted in HER2+ breast cancer cell lines with or without PIK3CA mutations, which lead to constitutive activation of the PI3K pathway. PIK3CA mutations played important roles in resistance to single-agent anti-HER2 therapy in breast cancer cell lines. Combination therapy of a HER2 inhibitor and an AKT inhibitor, as well as other PI3K pathway inhibitors, could overcome the therapeutic limitations associated with single-agent anti-HER2 treatment in PIK3CA-mutant HER2+ breast cancer cell lines. Furthermore, expression of phosphorylated 4E-binding protein 1 (p4EBP1) following the treatment correlated with the antiproliferative activities of the combination, suggesting that p4EBP1 may have potential as a prognostic and/or efficacy-linking biomarkers for these combination therapies in patients with HER2+ breast cancer. These findings highlight potential clinical strategies using combination therapy to overcome the limitations associated with single-agent anti-HER2 therapies in patients with HER2+ breast cancer.
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DOI：
10.1093/jnci/djt121
发表时间：
2013-07-03
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Loi S;Michiels S;Lambrechts D;Fumagalli D;Claes B;Kellokumpu-Lehtinen PL;Bono P;Kataja V;Piccart MJ;Joensuu H;Sotiriou C
通讯作者：
Sotiriou C
影响因子：
45.3
作者：
Baselga, Jose;Cortes, Javier;Swain, Sandra M.
通讯作者：
Swain, Sandra M.
影响因子：
8.4
作者：
Bang, Y-J;Kang, Y-K;Ajani, J. A.
通讯作者：
Ajani, J. A.
影响因子：
8.8
作者：
Janku F;Hong DS;Fu S;Piha-Paul SA;Naing A;Falchook GS;Tsimberidou AM;Stepanek VM;Moulder SL;Lee JJ;Luthra R;Zinner RG;Broaddus RR;Wheler JJ;Kurzrock R
通讯作者：
Kurzrock R
磷脂酰肌醇3-激酶过度激活导致拉帕替尼的抗性，这是由mTOR/磷脂酰/磷脂酰肌醇3-激酶抑制剂NVP-BEZ235逆转的。
影响因子：
11.2
作者：
Eichhorn PJ;Gili M;Scaltriti M;Serra V;Guzman M;Nijkamp W;Beijersbergen RL;Valero V;Seoane J;Bernards R;Baselga J
通讯作者：
Baselga J