Oncogenic mutation of PIK3CA in small cell lung carcinoma: A potential therapeutic target pathway for chemotherapy-resistant lung cancer
Oncogenic mutation of PIK3CA in small cell lung carcinoma: A potential therapeutic target pathway for chemotherapy-resistant lung cancer
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DOI：
10.1016/j.canlet.2009.03.038
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发表时间：
2009-10-08
期刊：
影响因子：
9.7
通讯作者：
Hirohashi, Setsuo
中科院分区：
文献类型：
--
作者：
Shibata, Tatsuhiro;Kokubu, Akiko;Hirohashi, Setsuo
肺癌是世界上最常见的癌症之一。本研究针对临床预后较差的小细胞肺癌（SCLC），试图阐明潜在的治疗分子靶点。靶特异性突变搜索显示，13个SCLC细胞系中的3个和15个原发SCLC中的2个存在PIK3CA基因突变。通过引入这些突变的PIK3CA cdna，我们建立了人工“PIK3CA成瘾”细胞，发现位于PIK3CA下游的AKT信号的小分子抑制剂Tricribine显著抑制了这些细胞的生长和集落形成活性。利用癌细胞系，我们进一步发现PIK3CA突变的SCLC细胞比PIK3CA野生型细胞对Tricribine更敏感。此外，我们发现pik3ca突变的SCLC细胞的顺铂耐药亚组对Tricribine同样敏感。本研究首次揭示了SCLC中PIK3CA的改变，我们的研究结果表明，抗akt分子治疗可能对SCLC的一个亚群有效，这表明特定基因的激活，如PIK3CA突变，根据个体治疗靶点通路的激活状态对SCLC进行遗传分层可能在临床上是有益的，特别是对化疗耐药/复发肿瘤。2009爱思唯尔爱尔兰有限公司版权所有。
Lung cancer is one of the most prevalent cancers worldwide. This study focused on small cell lung cancer (SCLC), which has a poor clinical prognosis, and attempted to elucidate potential therapeutic molecular targets. A target-specific mutational search revealed mutation of the PIK3CA gene in three of 13 SCLC cell lines and two of 15 primary SCLCs. By introducing these mutant PIK3CA cDNAs, we established artificial "PIK3CA-addicted" cells and found that Tricribine, a small-molecule inhibitor of AKT signaling that is located downstream from PIK3CA, significantly inhibited the growth and colony formation activity of these cells. Using cancer cell lines, we further showed that PIK3CA-mutated SCLC cells are more sensitive to Tricribine than PIK3CA wild-type cells. Additionally, we found that a cisplatin-resistant subdone of PIK3CA-mutant SCLC cells was equally sensitive to Tricribine. This study for the first time uncovered PIK3CA alterations in SCLC, and our findings suggest that anti-AKT molecular therapy could be effective for a subgroup of SCLC, which shows activation of specific genes, such as PIK3CA mutation, and that genetic stratification of SCLC according to the activation status of individual therapeutic target pathways could be clinically beneficial, especially for chemotherapy-resistant/relapsing tumors. (C) 2009 Elsevier Ireland Ltd. All rights reserved.