Enhanced PI3K p110α signaling confers acquired lapatinib resistance that can be effectively reversed by a p110α-selective PI3K inhibitor.
Enhanced PI3K p110α signaling confers acquired lapatinib resistance that can be effectively reversed by a p110α-selective PI3K inhibitor.
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DOI：
10.1158/1535-7163.mct-13-0518
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发表时间：
2014-01
影响因子：
5.7
通讯作者：
Yu D
中科院分区：
文献类型：
--
作者：
Brady SW;Zhang J;Seok D;Wang H;Yu D
虽然HER 2靶向药物曲妥珠单抗和拉帕替尼改善了HER 2阳性乳腺癌患者的生存率，但对这些靶向治疗的耐药性是一个主要挑战。为了研究获得性拉帕替尼耐药的机制，我们通过延长两种HER 2阳性乳腺癌细胞系对拉帕替尼的暴露来产生获得性拉帕替尼耐药细胞模型。基因组学和蛋白质组学分析显示，拉帕替尼耐药乳腺癌细胞通过激活PI 3 K p110α突变和/或增加现有突变型p110α的蛋白表达获得额外的PI 3 K激活。拉帕替尼耐药细胞中p110α蛋白上调通过基因扩增或转录后上调发生。p110α（而非p110β）（上皮细胞中存在的另一种PI 3 K催化亚基）的敲低可抑制拉帕替尼耐药细胞的增殖，尤其是与拉帕替尼联合使用时。p110α-选择性PI 3 K抑制剂BYL 719和拉帕替尼联合给药可持续抑制拉帕替尼耐药异种移植物生长;该药物联合给药在小鼠中也耐受良好。从机制上讲，拉帕替尼加BYL 719的组合在耐药模型中比单独使用任何一种药物更有效地抑制Akt磷酸化，并且令人惊讶地抑制Erk磷酸化。这些结果表明，拉帕替尼耐药可通过p110α蛋白上调介导和/或突变诱导的PI 3 K激活发生。此外，一种组合靶向治疗，拉帕替尼加BYL 719，有效地克服了拉帕替尼在体内的耐药性，并可以在临床试验中进一步测试。最后，我们的研究结果表明，在某些情况下，p110β可能与拉帕替尼耐药有关。这允许使用p110α特异性PI 3 K抑制剂，因此可能使患者免于泛PI 3 K抑制的毒性，以获得最大剂量和疗效。
While the HER2-targeting agents trastuzumab and lapatinib have improved the survival of patients with HER2-positive breast cancer, resistance to these targeted therapies is a major challenge. To investigate mechanisms of acquired lapatinib resistance, we generated acquired lapatinib resistance cell models by extended exposure of two HER2-positive breast cancer cell lines to lapatinib. Genomic and proteomic analyses revealed that lapatinib-resistant breast cancer cells gained additional PI3K activation through activating mutation in PI3K p110α and/or increasing protein expression of existing mutant p110α. p110α protein up-regulation in lapatinib-resistant cells occurred through gene amplification or post-transcriptional upregulation. Knockdown of p110α, but not p110β, the other PI3K catalytic subunit present in epithelial cells, inhibited proliferation of lapatinib-resistant cells, especially when combined with lapatinib. Lapatinib-resistant xenograft growth was inhibited persistently by combination treatment with the p110α-selective PI3K inhibitor BYL719 and lapatinib; the drug combination was also well-tolerated in mice. Mechanistically, the combination of lapatinib plus BYL719 more effectively inhibited Akt phosphorylation and, surprisingly, Erk phosphorylation, than either drug alone in the resistance model. These findings indicate that lapatinib resistance can occur through p110α protein upregulation-mediated, and/or mutation-induced, PI3K activation. Moreover, a combinatorial targeted therapy, lapatinib plus BYL719, effectively overcame lapatinib resistance in vivo and could be further tested in clinical trials. Finally, our findings indicate that p110β may be dispensable for lapatinib resistance in some cases. This allows the usage of p110α-specific PI3K inhibitors and thus may spare patients the toxicities of pan-PI3K inhibition to allow maximal dosage and efficacy.