(below) palbociclib treatment
Images courtesy of Iris Uras
and Vetmeduni Vienna
Palbociclib, a CDK4/6 kinase inhibitor approved to treat breast cancer, could also be used to treat acute myeloid leukemia (AML), according to research published in Blood.
The drug induced apoptosis in FLT3-mutant AML cells and inhibited tumor growth in mouse models of FLT3-ITD+ AML.
Palbociclib also demonstrated synergy with a range of FLT3 inhibitors.
The researchers said these results can be explained by the fact that CDK6 is “absolutely required” for the viability of FLT3-dependent leukemic cells and FLT3-ITD-induced leukemogenesis.
“We found a novel therapeutic window that attacks the dependency of a cancer cell on its growth regulator,” said study author Iris Uras, PhD, of Vetmeduni Vienna in Austria.
Dr Uras and her colleagues first found that palbociclib acts specifically on FLT3-ITD+ AML cells, inhibiting their viability in a dose-dependent manner. Palbociclib induced cell-cycle arrest and apoptosis in these cells.
Palbociclib also arrested tumor growth in mouse models of FLT3-ITD+ AML, significantly decreasing tumor size when compared to untreated controls (P<0.05).
Further investigation revealed that CDK6—but not CDK4—directly regulates FLT3 expression.
CDK6 acts as a transcriptional regulator of FLT3 and the serine threonine kinase PIM1, which also plays a role in leukemogenesis. As palbociclib inhibits CDK6, it downregulates FLT3 and reduces PIM1 transcription.
To build upon these findings, the researchers tested palbociclib in combination with FLT3 inhibitors.
They observed “pronounced in vitro synergy” between palbociclib and TCS-359, tandutinib, and quizartinib in FLT3-ITD+ AML cell lines and samples from patients with FLT3-ITD+ AML.
“We are attacking FLT3 from two sides there—blocking its expression and inhibiting its activity,” Dr Uras said. “A combination therapy could be a breakthrough for many patients suffering from leukemia.”
