Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment

Abstract

Phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) are two key components of the PI3K/Akt/mTOR signaling pathway. This signal transduction cascade regulates a wide range of physiological cell processes, that include differentiation, proliferation, apoptosis, autophagy, metabolism, motility, and exocytosis. However, constitutively active PI3K/Akt/mTOR signaling characterizes many types of tumors where it negatively influences response to therapeutic treatments. Hence, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors may improve cancer patient outcome. The PI3K/Akt/mTOR signaling cascade is overactive in acute leukemias, where it correlates with enhanced drug-resistance and poor prognosis. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds targeting the catalytic site of both kinases. In preclinical models, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against acute leukemia cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin. At variance with rapamycin, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenic protein translation. Therefore, they strongly reduced cell proliferation and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors may represent a promising option for future targeted therapies of acute leukemia patients.

Effects of NVP‑BEZ235, a dual phosphatidylinositol�3-kinase/mammalian target of rapamycin inhibitor, on HTLV-1-infected T-cell lines

“…The PI3K/Akt/mTOR pathway plays an important role in cell proliferation, and is thus an interesting target for the treatment of various cancers, including hematological malignancies (26). Loss of function of phosphatases, most notably PTEN, which regulate this pathway, has been demonstrated in ATL (6).…”

Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia

“…Importantly, a body of evidence suggests that constitutive activation of mTORC1 in AML is independent of PI3K which in turn can be constitutively fully activated in an mTOR-independent manner. 29 Previous studies have demonstrated that PI3K/Akt inhibitors caused decreased expression of many proteins including survivin 17,18,[30][31][32] in solid tumors and hematologic malignancies. Additionally, it has been shown in a mouse model that internal tandem duplication of Flt3 regulates survivin expression via PI3K/Akt leading to aberrant progenitor cell proliferation and promoting leukemogenesis.…”

“…2,3,35 The prognostic impact of the PI3K/Akt/CytSurWT pathway described in this study provides important information for the clinical management of AML patients. PI3K/Akt inhibitors (MK2206, BKM120, LY2181308) or dual PI3K/mTOR inhibitors, as well as survivin antagonists (terameprocol EM-1421, CWP232291) are currently being evaluated in clinical trials, in order to improve results obtained with conventional chemotherapy in AML 29 . As a consequence of our findings, the PI3K/Akt/CytSurWT activated pathway represents a favorable prognostic factor identifying patients likely to achieve a long-term cure with conventional chemotherapy regimens.…”

Application and interpretation of current autophagy inhibitors and activators

“…In mammalian cells, there are three classes of PI3Ks. Class I PI3K is an inhibitor of autophagy [79] . Class II PI3K activity is thought to have no relevance to autophagic control.…”