Two feedback loops have been described, with S6K and JNK, which in the insulin-induced PI3K activation via IRS Tenuate 105,107. S6K Knockout Mice or JNK show an increase in Insulinsensitivit t in response to fat 108, 109 St These feedback loops Ren can have dramatic effects on response to the drug, such as the reaction of certain tumors is rapalogs. When XAV-939 mTOR is activated, it can be a signaling cascade initiated by S6K1 in which a feedback loop that negatively regulates the activity of t PI3K/AKT results. Thus, when the tumors in this loop is to be treated with activated rapalogs can t, the net effect high AKT activity, Which in turn can ultimately enhance tumor growth be 110th PI3K or AKT inhibitor should not be affected by this issue, but may suffer from problems due to crosstalk with other railways.
More specifically, for cancers with mutated RTK or oncogenes such as Ras, Raf activate both MAPK and PI3K, blocking the PI3K pathway for reference chlich regulate the MAPK pathway Raf because both Kan cross Le inhibitory effect 111th Raf MAPK pathway in turn can stimulate tumor growth, against the effect of the inhibition of PI3K. Pandolfi and colleagues have recently shown that mTORC1 inhibition of activation of MAPK in a PI3K dependent-Dependent results, providing another example of a feedback loop and signaling crosstalk 112th As discussed below, the combined inhibition of the two signal processing paths this problem l Sen. The identification of biomarkers that predict drug response inhibitors of PI3K, as all targeted therapies, it is crucial to pr Predictive biomarkers of response to drugs to develop medically treatable.
Those who develop drugs say to achieve the targets of the PI3K pathway, and those who can respond to the patients most likely to predict k: k biomarkers can be divided into two categories. Easy-to tissue, such as skin, hair follicles, and peripheral mononuclear Ren cells as a surrogate tissue were used to determine the effect of PI3K inhibitors currently in clinical trials assessment obtained 113th Molecular markers of inhibition of PI3K are usually in clinical phosphorylated AKT and phospho S6K1 levels used in tissue biopsies of these alternatives and, if possible to change the tumor tissue. However, there is great variability e t Its robustness and reproducibility of biomarkers in monitoring the effectiveness of PI3K inhibitors.
Therefore, the identification of new biomarkers and m Possibly, more robust one U Only important part of the pr Clinical development of PI3K inhibitors and in the conduct and analysis of clinical trials with these inhibitors. Preclinical studies have shown that inhibition of PI3K/AKT by measuring blood levels of insulin, the result of the St Tion of insulin by the PI3K/Akt signaling pathway 64, 98 increased, 114 Ht can be evaluated, 115 Studies in M nozzles Associated with a genetic or inactivation PI3Ks AKT 93, 95, 98, proposed 114 also that Ver changes In the levels of glucose in the blood can be exploited clinically, in response to the inhibition of PI3K, but the first clinical data suggest that these effects may be transient and difficult to measure.