The FLT3 tyrosine kinase is the most frequent mutation found in acute myeloid leukemia (AML), and targeting CDK6 with palbociclib may be an effective strategy against AML. CDK6 is upstream of FLT3, so blocking CDK6 leads to downregulating FLT3.1
The most frequent form of leukemia is AML. Prognosis is poor with high mortality despite advances in chemotherapy and hematopoietic stem cell transplantation.
Previous efforts sought to treat AML by blocking FLT3 because its mutations are important in the progression of AML. Unfortunately, FLT3 kinase inhibitors have had limited clinical impact. Reponses in patients with FLT3 mutations are transient and resistant clones emerge rapidly.
In this study, Iris Uras, of the University of Veterinary Medicine in Vienna, Austria, and colleagues note that the tumor-promoting factor CDK6 directly regulates and initiates production of FLT3, thus causing AML.
“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” explained Uras. The compound, from breast cancer therapy, palbociclib deprives the cancer cells of nutrients. AML cancer cells carrying the mutation died immediately in the experiments. The drug does not affect cells lacking the mutation, indicating that it is highly specific.
An advantage of palbociclib is that it was approved to treat breast cancer in 2015; therefore, clinical studies in patients can be rapidly initiated, as its safety profile is already known.
Combining palbociclib with compounds that block FLT3 kinase activity increases its efficacy.
“We are attacking FLT3 from 2 sides there, by blocking its expression and inhibiting its activity. A combination therapy could be a breakthrough for many patients suffering from leukemia,” Uras noted.
1. Uras IZ, Walter GJ, Scheicher R, et al. Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6 [published online April 20, 2016]. Blood. doi:10.1182/blood-2015-11-683581.