Inhibition of PI3K/mTOR Pathways with GDC-0980 in Pediatric Leukemia: Impact on Abnormal FLT-3 Activity and Cooperation with Intracellular Signaling Targets.

Abstract

BACKGROUND:

GDC-0980 is a selective small molecule inhibitor of class I PI3K and mTOR pathway with a potent anti-proliferative activity.

OBJECTIVE:

We set out to evaluate the efficacy of GDC-0980, in pre-clinical studies, against pediatric leukemia cells.

METHODS:

The anti-neoplastic activity of GDC-0980 was evaluated in vitro using five different pediatric leukemia cells.

RESULTS:

Our data show that GDC-0980 significantly inhibited the proliferation of leukemia cell lines, KOPN8 (IC50, 532 nM), SEM (IC50,720 nM), MOLM-13 (IC50,346 nM), MV4;11 (IC50,199 nM), and TIB-202 (IC50, 848 nM), compared to normal control cells (1.23 µM). This antiproliferative activity was associated with activation of cellular apoptotic mechanism characterized by a decrease in Bcl-2 protein phosphorylation and enhanced PARP cleavage. Western blot analyses of GDC-0980 treated cells also showed decreased phosphorylation levels of mTOR, Akt and S6, but not ERK1/2. Notably, FLT3 phosphorylation was decreased in Molm-13 and MV4;11 cells following the application of GDC-0980. We further examined cellular viability of GDC-0980-treated primary leukemia cells isolated from pediatric leukemia patients. This study revealed a potential therapeutic effect of GDC-0980 on two ALL patients (IC50's, 1.23 and 0.625 µM, respectively). Drug combination analyses of GDC-0980 demonstrated a synergistic activity with the MEK inhibitor Cobimetinib (MV4-11; 11, CI, 0.25, SEM, CI, 0.32, and TIB-202, CI, 0.55) and the targeted FLT3 inhibitor, Crenolanib (MV4-11; 11, CI, 0.25, SEM, CI, 0.7, and TIB-202, CI, 0.42).

CONCLUSION:

These findings provide initial proof-of-concept data and rationale for further investigation of GDC-0980 in selected subgroups of pediatric leukemia patients.

• Authors: Abdulhameed Al-Ghabkari, Maneka A Perinpanayagam, Aru Narendran
• Journal: Current cancer drug targets (Curr Cancer Drug Targets) Vol. 19 Issue 10 Pg. 828-837 ( 2019) ISSN: 1873-5576 [Electronic] Netherlands
• PMID: 30914027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright© Bentham Science Publishers; For any queries, please email at [email protected].

Chemical References

• 1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one
• BCL2 protein, human
• Bridged Bicyclo Compounds, Heterocyclic
• PI3KCA protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidines
• Transcription Factors
• MTOR protein, human
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• TOR Serine-Threonine Kinases

Topics

• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cell Line, Tumor
• Cell Survival
• Child
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (antagonists & inhibitors)
• Pyrimidines (pharmacology)
• Signal Transduction
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Transcription Factors (antagonists & inhibitors)
• fms-Like Tyrosine Kinase 3 (genetics, metabolism)