Combination Of Kinase Inhibitors
Yaktapour N, Dierks C, Pfeifer D, et al.
Key Points:
- Investigators provide analysis of various B-Raf inhibitors in primary human CLL cells; alone or in combination with MEK (U0126), dual PI3K/mTOR inhibitor (BEZ235), and IGF1R inhibitors (AG1024)
- B-Raf inhibitors (PLX4720/dabrafenib), lower doses (1-5µM) of sorafenib induced paradoxical ERK activation and enhanced viability.
- Combining B-Raf inhibitors and MEK inhibitor or dual PI3K/mTOR inhibitor reduced ERK phosphorylation and significantly enhanced rates of cell death
- IGF1R inhibitors + suboptimal sorafenib doses and observed significantly enhanced cell death for combinations AG1024 and sorafenib (p<0,0001) as well as PPP and sorafenib (p<0,0001).
Implications:
- Raf inhibitors cause paradoxical ERK activation in CLL cells with unmated BRAF
- Sorafenib plasma concentrations should be monitored when used for treatment of CLL; lower plasma levels might promote paradoxical ERK activation and CLL progression
- Combining kinase inhibitors may potentially overcome paradoxical ERK activation.
View the original abstract on the ASH website.
