Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers.
Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers.
复制标题
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
作者：
激活磷酸肌醇3-激酶（PI3K）的体细胞突变已在p110-α催化亚基（PIK3CA）中鉴定出来。尽管PIK3CA突变体在体外转化，但在基因工程的小鼠模型中尚未评估其致癌潜力。抑制剂已开始启动，在本研究中，它们的效率是否仅限于特定的遗传性恶性肿瘤，我们设计了一种诱导的比特氏菌小鼠模型，该模型通过p110-αH1047R的表达来启动和维持肺腺癌在具有NVP-BEZ235的这些肿瘤中，临床发育中的双PAN PI3K/mTOR抑制剂导致了明显的肿瘤回归PET-CT，MRI和显微镜检查。在缩小这些K-RAS突变体癌症时，这些体内研究表明PI3K/MTOR途径的抑制剂可能活跃于PIK3CA突变的癌症中，并且，当与MEK抑制剂结合使用时，可以有效治疗K-RAS突变的肺癌。
Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the PIK3CA mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered an inducible bitransgenic mouse model that develops lung adenocarcinomas initiated and maintained by expression of p110-α H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan PI3K/mTOR inhibitor in clinical development, led to marked tumor regression as shown by PET-CT, MRI and microscopic examination. In contrast, mouse lung cancers driven by mutant K-Ras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a MEK inhibitor, ARRY-142886, there was dramatic synergy in shrinking these K-Ras mutant cancers. These in vivo studies suggest that inhibitors of the PI3K/mTOR pathway may be active in cancers with PIK3CA mutations, and, when combined with MEK inhibitors, may effectively treat K-RAS mutated lung cancers.
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影响因子：
11.5
作者：
Perez-Tenorio, Gizeh;Alkhori, Liza;Stal, Olle
通讯作者：
Stal, Olle
影响因子：
5.7
作者：
Maira, Sauveur-Michel;Stauffer, Frederic;Garcia-Echeverria, Carlos
通讯作者：
Garcia-Echeverria, Carlos
DOI：
10.1073/pnas.0504378102
发表时间：
2005-07-19
影响因子：
11.1
作者：
Luo, J;Sobkiw, CL;Cantley, LC
通讯作者：
Cantley, LC
影响因子：
56.9
作者：
Fruman, DA;Snapper, SB;Cantley, LC
通讯作者：
Cantley, LC
影响因子：
50.3
作者：
She, QB;Solit, DB;Rosen, N
通讯作者：
Rosen, N