State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100191, China.
Cell Death Dis. 2013 Sep 26;4(9):e814. doi: 10.1038/cddis.2013.312.
The exact influence of statins on gefitinib resistance in human non-small cell lung cancer (NSCLC) cells with KRAS mutation alone or KRAS/PIK3CA and KRAS/PTEN comutations remains unclear. This work found that transfection of mutant KRAS plasmids significantly suppressed the gefitinib cytotoxicity in Calu3 cells (wild-type KRAS). Gefitinib disrupted the Kras/PI3K and Kras/Raf complexes in Calu3 cells, whereas not in Calu3 KRAS mutant cells. These trends were corresponding to the expression of pAKT and pERK in gefitinib treatment. Atorvastatin (1 μM) plus gefitinib treatment inhibited proliferation, promoted cell apoptosis, and reduced the AKT activity in KRAS mutant NSCLC cells compared with gefitinib alone. Atorvastatin (5 μM) further enhanced the gefitinib cytotoxicity through concomitant inhibition of AKT and ERK activity. Atorvastatin could interrupt Kras/PI3K and Kras/Raf complexes, leading to suppression of AKT and ERK activity. Similar results were also obtained in comutant KRAS/PTEN or KRAS/PIK3CA NSCLC cells. Furthermore, mevalonate administration reversed the effects of atorvastatin on the Kras/Raf and Kras/PI3K complexes, as well as AKT and ERK activity in both A549 and Calu1 cells. The in vivo results were similar to those obtained in vitro. Therefore, mutant KRAS-mediated gefitinib insensitivity is mainly derived from failure to disrupt the Kras/Raf and Kras/PI3K complexes in KRAS mutant NSCLC cells. Atorvastatin overcomes gefitinib resistance in KRAS mutant NSCLC cells irrespective of PIK3CA and PTEN statuses through inhibition of HMG-CoA reductase-dependent disruption of the Kras/Raf and Kras/PI3K complexes.
单独 KRAS 突变或 KRAS/PIK3CA 和 KRAS/PTEN 共突变的人非小细胞肺癌（NSCLC）细胞中他汀类药物对吉非替尼耐药的确切影响尚不清楚。本研究发现，转染突变型 KRAS 质粒可显著抑制 Calu3 细胞（野生型 KRAS）中吉非替尼的细胞毒性。吉非替尼破坏了 Calu3 细胞中的 Kras/PI3K 和 Kras/Raf 复合物，但在 Calu3 KRAS 突变细胞中则没有。这些趋势与吉非替尼处理后 pAKT 和 pERK 的表达相对应。与单独使用吉非替尼相比，阿托伐他汀（1μM）加吉非替尼治疗可抑制增殖、促进细胞凋亡，并降低 KRAS 突变型 NSCLC 细胞中的 AKT 活性。阿托伐他汀（5μM）通过同时抑制 AKT 和 ERK 活性，进一步增强了吉非替尼的细胞毒性。阿托伐他汀可中断 Kras/PI3K 和 Kras/Raf 复合物，从而抑制 AKT 和 ERK 活性。在共突变 KRAS/PTEN 或 KRAS/PIK3CA NSCLC 细胞中也得到了类似的结果。此外，给予甲羟戊酸可逆转阿托伐他汀对 A549 和 Calu1 细胞中 Kras/Raf 和 Kras/PI3K 复合物以及 AKT 和 ERK 活性的影响。体内结果与体外结果相似。因此，突变型 KRAS 介导的吉非替尼不敏感主要源于 KRAS 突变 NSCLC 细胞中不能破坏 Kras/Raf 和 Kras/PI3K 复合物。阿托伐他汀通过抑制 HMG-CoA 还原酶依赖性破坏 Kras/Raf 和 Kras/PI3K 复合物，克服了 KRAS 突变型 NSCLC 细胞对吉非替尼的耐药性，而与 PIK3CA 和 PTEN 状态无关。
