Bringing target-matched PI3King from the bench to the clinic
نویسنده
چکیده
Increased signaling through the phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway occurs in diverse malignancies. In cancer, the PI3K/AKT/mTOR pathway can be activated by mutations in several oncogenes such as PIK3CA, PIK3R1, AKT, TSC1/2, LKB1 and PTEN (Fig. 1). Most activating mutations occur in the helical or kinase domain of the PIK3CA gene. Preclinical models demonstrated that mutations in PIK3CA have oncogenic potential and can also be associated with sensitivity to PI3K/AKT/mTOR inhibitors. In a human non-small cell lung cancer (NSCLC) xenograft model, PIK3CA mutation H1047R was associated with response to the dual PI3K and mTOR kinase inhibitor BEZ235. Similarly, breast cells with the same mutation demonstrated reduced proliferation compared with breast cells with wildtype (wt) PIK3CA. In addition, early clinical data from histology-independent protocols suggested that PIK3CA mutations could be associated with sensitivity to therapies targeting PI3K/AKT/mTOR signaling in subsets of patients with advanced cancers. The reported response rate of these patients in early-phase clinical trials was approximately 30%, which is less than that with some other molecularly matched therapies, but significantly more than the traditional response rates of 4% to 6% observed in this patient population. Preclinical models also demonstrated that KRAS mutations can be associated with resistance to PI3K/AKT/mTOR Bringing target-matched PI3King from the bench to the clinic
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عنوان ژورنال:
دوره 12 شماره
صفحات -
تاریخ انتشار 2013