In some cases, the PI3K pathway is also responsible for the escape of cells from immune system. A hyperactivation of Akt was found in a immune-resistant human papillomavirus type 16 (HPV-16) tumor cell line. It was thought to be responsible for the enhenced resistance of these cells to CD8 T-cell-mediated apoptosis . Interestingly, cancer cells was found to suppress immune by some manners, including releasing immune-suppressive cytokines and chemokines, or inducing lymphocyte apoptosis [43; 64].
Due to the super activation of the PI3K signaling pathway in cancer cells, uncontrollable proliferation, survival and angiogenesis in various human malignancies had an opportunity to occur. Enormous efforts have been made for developing medicines targeting PI3K / Akt / mTOR pathway.
In the following research works, isoform-selective PI3K inhibitors were reported. PI‑103 is able to inhibit both p110a and mTOR in glioma cells . A Phase I study showed that a selective inhibitor of p110δ called CAL‑101 could be helpful with the treatment of hematologic malignancies in patients . PX‑866, a pan-PI3K inhibitor, showed a mild side effect in part of the patients with solid tumors, such as squamous cell skin cancer and melanoma . GDC0941, another pan-PI3K inhibitor, also displayed desirable anticancer effect in sarcoma, ovarian cancer and endometrial cancer patients .
Under some conditions, inhibiting more than one target of PI3K pathway might lead to better effect. BEZ235, dual PI3K/mTOR inhibitor, inhibits Class I PI3K isoforms and mTOR kinase activity by binding to the ATP-binding pocket of PI3K. It has strong anti-proliferative effect on tumor xenografts and is now under Phase I/II clinical trials for breast cancer and endometrial cancer .
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