Dysregulation of PI3K is common in the progression of various diseases, including, but not limited to, tumors, Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, and acute myelogenous leukemia.
We have recently revealed that FLT3-ITD confers resistance to the PI3K/AKT pathway inhibitors by protecting the mTORC1/4EBP1/Mcl-1 pathway through Pim kinases induced by STAT5 activation in AML.
Given that histone deacetylase inhibitors have been shown to synergize with PI3K inhibitors in preclinical AML models, we investigated the novel dual-acting PI3K and histone deacetylase inhibitor CUDC-907 in AML cells both <i>in vitro</i> and <i>in vivo</i> We demonstrated that CUDC-907 induces apoptosis in AML cell lines and primary AML samples and shows <i>in vivo</i> efficacy in an AML cell line-derived xenograft mouse model.
In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.
New targeted therapies for hematological malignancy include chimeric antigen receptor T cells (CAR T cells), Bi-specific T-cell Engager (BiTE) blinatumomab, and the antibody-drug conjugate (ADC) of calicheamicin inotuzumab ozogamicin for acute lymphoblasic leukemia (ALL) and lymphoma; the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and phosphatidylinositol 3-kinase (PI3Kδ) inhibitor idelalisib for lymphoma and graft-versus-host disease (GVHD); FMS-like tyrosine kinase 3 (FLT3) inhibitors, such as midostaurin, sorafenib and gilteritinib for acute myeloid leukemia (AML); and the BCL-2 inhibitor venetoclax for a range of hematological malignancies including lymphoma and leukemia.
Inhibition of the mTORC1 pathway has met with limited success in AML due to multiple resistance mechanisms including direct insensitivity of the mTORC1 complex, feedback activation of the PI3k/Akt signaling network, insulin growth factor-1 (IGF-1) activation of PI3K, and others.
Inositol polyphosphate 4-phosphatase type II (INPP4B), a new factor in the phosphoinositide-3 kinase (PI3K) pathway-associated cancers, has been recently found a clinically relevant role in AML.
Thus, combined inhibition of PI3Kδ and FLT3 may be a promising strategy in FLT3-activated AML, particularly for patients with FLT3-inhibitor-resistant mutations.
These findings argue that dual BCL-2 and PI3K inhibition warrants further evaluation in AML.<b>Significance:</b> Combined treatment with clinically relevant PI3K and BCL-2 inhibitors may prove effective in the treatment of acute myeloid leukemia.<i></i>.
In this study, we show that while inhibition of PI3K, mTOR, and ERK showed superior induction of cell death compared to inhibition of PI3K and mTOR, the levels of cell death were modest in some AML cell lines and primary patient samples tested.
Two acute myeloid leukemia patient subsets are identified based on the constitutive PI3K-Akt-mTOR signaling of their leukemic cells; a functional, proteomic, and transcriptomic comparison.
The aim of this study was to investigate the role of the PI3K/Akt signaling pathway in ATOtreated human acute myeloid leukemia (HL-60) cells and in ATO-resistant clones.
In the present study, the antiproliferative effects of PI3K inhibitor ZSTK474 on AML cell HL60 and the adriamycin (ADR)-resistant HL60/ADR cells were investigated.
Furthermore, the inhibition of FLT3 and PI3K resulted in reduced GLI protein expression and promotor activity in FLT3-mutated but not in FLT3 wildtype AML cell lines in western blotting and GLI1/2 promoter assays supporting our hypothesis of non-canonical GLI activation via FLT3.In summary, FLT3-mutated in contrast to FLT3 wildtype cells or normal human hematopoietic progenitor cells are exquisitely sensitive to combined inhibition by FLT3, PI3K and GLI1/2 overcoming some of the limitations of current FLT3 directed therapy in AML.
The results demonstrate that targeting both PI3Kδ and PI3Kγ to inhibit AML-BMSC interactions provides a biologic rationale for the pre-clinical evaluation of IPI-145 in AML.