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

Background: GDC-0980 is a targeted small molecule inhibitor that selectively blocks class I PI3K and mTOR pathways, exhibiting strong anti-proliferative effects.

Objective: This study aimed to assess the efficacy of GDC-0980 in preclinical models of pediatr leukemia.

Methods: The anti-cancer effects of GDC-0980 were tested in vitro using five different pediatric leukemia cell lines.

Results: GDC-0980 significantly inhibited the proliferation of the 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 (IC50: 1.23 µM). This inhibition was linked to the activation of apoptotic pathways, evidenced by reduced Bcl-2 protein phosphorylation and increased PARP cleavage. Western blot analysis of GDC-0980-treated cells showed decreased phosphorylation of mTOR, Akt, and S6, but not ERK1/2. Additionally, FLT3 phosphorylation was reduced in MOLM-13 and MV4;11 cells following GDC-0980 treatment. Further testing on primary leukemia cells isolated from pediatric patients revealed potential therapeutic effects of GDC-0980, with IC50 values of 1.23 µM and 0.625 µM in two acute lymphoblastic leukemia (ALL) patients. Combination drug analyses showed that GDC-0973 had synergistic effects when used with the MEK inhibitor Cobimetinib (MV4-11 CI: 0.25, SEM CI: 0.32, TIB-202 CI: 0.55) and the FLT3 inhibitor Crenolanib (MV4-11 CI: 0.25, SEM CI: 0.7, TIB-202 CI: 0.42).

Conclusion: These findings provide preliminary proof-of-concept data supporting further investigation of GDC-0980 in specific subgroups of pediatric leukemia patients.