Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Cancer Lett. 2017 Oct 10;406:47-53. doi: 10.1016/j.canlet.2017.07.028. Epub 2017 Aug 7.
More than 25% of non-small cell lung cancers (NSCLCs) carry mutations in KRAS, one of the most common oncogenic drivers in this disease. KRAS-mutant NSCLC responds poorly to currently available therapies; therefore, novel treatment strategies are needed. Here, we describe a particularly promising targeted therapeutic strategy against KRAS mutation-harboring NSCLC intrinsically resistant to treatment by PI3K inhibition. We found that intrinsic resistance to PI3K inhibition derived from RAF/MEK/ERK and RSK activation, bypassing blockage of the PI3K/AKT/mTOR pathway. The HSP90 inhibitor AUY922 suppressed both PI3K/AKT/mTOR and RAF/MEK/ERK signaling, rendering cells sensitive to a PI3K inhibitor (omipalisib, GSK458). Combining these two drugs achieved a synergistic effect, even using only sub-therapeutic concentrations. Dual inhibition of the HSP90 and PI3K signaling pathways with sub-therapeutic doses of these combined anticancer drugs may represent a potent treatment strategy for KRAS-mutant NSCLC with intrinsic resistance to PI3K inhibition.
超过 25%的非小细胞肺癌（NSCLC）存在 KRAS 突变，KRAS 是该疾病中最常见的致癌驱动基因之一。KRAS 突变型 NSCLC 对目前可用的治疗方法反应不佳；因此，需要新的治疗策略。在这里，我们描述了一种针对 KRAS 突变型 NSCLC 的特别有前途的靶向治疗策略，该策略固有地对 PI3K 抑制治疗具有抗性。我们发现，PI3K 抑制的内在抗性源于 RAF/MEK/ERK 和 RSK 的激活，从而绕过了 PI3K/AKT/mTOR 途径的阻断。HSP90 抑制剂 AUY922 抑制了 PI3K/AKT/mTOR 和 RAF/MEK/ERK 信号通路，使细胞对 PI3K 抑制剂（omipalisib，GSK458）敏感。即使使用亚治疗浓度，这两种药物的联合使用也达到了协同作用。用这些联合抗癌药物的亚治疗剂量双重抑制 HSP90 和 PI3K 信号通路，可能代表了对 PI3K 抑制固有抗性的 KRAS 突变型 NSCLC 的一种有效治疗策略。
