Novel Agent Under Study in CLL: Dual Inhibitory Activity Reported
Posted: Friday, April 2, 2021
Researchers are studying a small-molecule multikinase inhibitor (TG02), which appears to have dual inhibitory activity on the chronic lymphocytic leukemia (CLL) survival pathway and B-cell receptor (BCR) signaling pathway. These investigative findings with therapeutic implications were published by William Plunkett, PhD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues in Blood Cancer Journal.
The team utilized blood samples from 84 patients with CLL, 3 healthy control donors, plus BAX/BAK double knockout murine cell lines. Cells were incubated with TG02 and assessed for viability and nuclear factor kappa B (NK-kB) activity. Finally, TG02 was combined with venetoclax or ibrutinib, and cell death was measured.
Researchers found that TG02 was toxic to primary CLL cells via interference with the mitochondrial membrane potential. TG02 did not seem toxic to BAX/BAK knockout cells, indicating these proteins are required for TG02-mediated apoptosis. The efficacy of TG02 in killing CLL cells did not appear to be dependent on CLL prognostic factors, including loss of TP53 loci or Rai stages 3 and 4.
Incubation of cells with TG02 led to a reduction in phosphorylation of RNA polymerase II via inhibition of cyclin-dependent kinase 9. This led to subsequent inhibition of RNA synthesis. TG02 also reduced the mRNA level of the antiapoptotic protein MCL1 by more than 80% after 4 hours of incubation. CLL samples had varied sensitivities to TG02, which also inhibits the BCR signaling pathway members, including Lck and Fyn, and blocked BCR-crosslinking activation of NF-κB.
A dose-response to TG02 was measured in CLL cells both before and 4 weeks after ibrutinib therapy. The investigators found that CLL cells remained sensitive to TG02 after lymphocytosis. Additionally, CLL cells refractory to ibrutinib appeared to respond similarly to nonrefractory cells when exposed to TG02.
Disclosure: Francis Burrows, PhD, is employed by Tragara Pharmaceuticals. All other authors reported no conflicts of interest.