Holland William S, Chinn Danielle C, Lara Primo N, Gandara David R, Mack Philip C
Comprehensive Cancer Center, University of California, Davis, 4501 X Street, Suite 3016, Sacramento, CA, 95817, USA.
J Cancer Res Clin Oncol. 2015 Apr;141(4):615-26. doi: 10.1007/s00432-014-1855-4. Epub 2014 Oct 17.
Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance.
The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance.
The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested.
These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.
表皮生长因子受体（EGFR）突变的非小细胞肺癌患者对厄洛替尼产生获得性耐药可能源于替代受体酪氨酸激酶的异常激活，如肝细胞生长因子（HGF）驱动的c-MET受体。我们试图确定抑制AKT信号传导是否能增强厄洛替尼的活性并消除HGF介导的耐药性。
在包含不同EGFR或KRAS异常的13种肺癌细胞系的大样本中，评估选择性AKT抑制剂MK-2206与厄洛替尼联合使用的效果。使用增殖试验、流式细胞术和免疫印迹法评估联合用药的活性。使用MEK抑制剂PD0325901确定MAP激酶途径在厄洛替尼耐药中的作用。
MK-2206与厄洛替尼联合使用可产生协同生长抑制作用，且与EGFR突变状态无关。在HGF阻断厄洛替尼抗增殖和细胞毒性作用的细胞系中，MK-2206可恢复细胞周期停滞，但依赖厄洛替尼的凋亡需要抑制MEK。在含T790M的H1975和测试的EGFR野生型细胞系中，抑制AKT和MEK均可导致与厄洛替尼无关的细胞死亡。
这些发现说明了联合信号转导抑制作为一种规避获得性厄洛替尼耐药的通用策略的潜在优势和挑战。
