1 research outputs found
Chemoproteomic Evaluation of Target Engagement by the Cyclin-Dependent Kinase 4 and 6 Inhibitor Palbociclib Correlates with Cancer Cell Response
Palbociclib
is a cyclin-dependent kinase (CDK) 4/CDK6 inhibitor
approved for breast cancer that is estrogen receptor (ER)-positive
and human epidermal growth factor receptor 2 (HER2)-negative. We profiled
palbociclib in cells either sensitive or resistant to the drug using
an ATP/ADP probe-based chemoproteomics platform. Palbociclib only
engaged CDK4 or CDK6 in sensitive cells. In resistant cells, no inhibition
of CDK4 or CDK6 was observed, although the off-target profiles were
similar in both cell types. Prolonged incubation of sensitive cells
with the compound (24 h) resulted in the downregulation of additional
kinases, including kinases critical for cell cycle progression. This
downregulation is consistent with cell cycle arrest caused by palbociclib
treatment. Both the direct and indirect targets were also observed
in a human tumor xenograft study using the COLO-205 cell line in which
phosphorylation of the retinoblastoma protein was tracked as the pharmacodyanamic
marker. Together, these results suggest that this probe-based approach
could be an important strategy toward predicting patient responsiveness
to palbociclib