The P16 (CDKN2Aink4a) gene is an endogenous CDK4/6 inhibitor.
Palbociclib (
PD0332991) is an anti-CDK4/6 chemical for
cancer treatment. P16 is most frequently inactivated by copy number deletion and DNA methylation in
cancers. It is well known that
cancer cells with P16 deletion are more sensitive to
palbociclib than those without. However, whether P16 methylation is related to
palbociclib sensitivity is not known. By analyzing public pharmacogenomic datasets, we found that the IC50 of
palbociclib in
cancer cell lines (n = 522) was positively correlated with both the P16 expression level and P16 gene copy number. Our experimental results further showed that
cancer cell lines with P16 methylation were more sensitive to
palbociclib than those without. To determine whether P16 methylation directly increased the sensitivity of
cancer cells to
palbociclib, we induced P16 methylation in the
lung cancer cell lines H661 and HCC827 and the
gastric cancer cell line BGC823 via an engineered P16-specific
DNA methyltransferase (P16-Dnmt) and found that the sensitivity of these cells to
palbociclib was significantly increased. The survival rate of P16-Dnmt cells was significantly lower than that of vector control cells 48 hrs post treatment with
palbociclib (10 μM). Notably,
palbociclib treatment also selectively inhibited the proliferation of the P16-methylated subpopulation of P16-Dnmt cells, further indicating that P16 methylation can increase the sensitivity of cells to this CDK4/6 inhibitor. These results were confirmed in an animal experiment. In conclusion, inactivation of the P16 gene by DNA methylation can increase the sensitivity of
cancer cells to
palbociclib.