Sarcomas are malignant
tumors accounting for a high percentage of
cancer morbidity and mortality in children and young adults. Surgery and
radiation therapy are the accepted treatments for most
sarcomas; however, patients with metastatic disease are treated with systemic
chemotherapy. Many
tumors display marginal levels of chemoresponsiveness and new treatment approaches are needed. Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many
cancer cell types depend on CDK4/6 activity. Thus, CDK4/6 activity appears to represent a promising therapeutic target for
cancer treatment. In the present work, we explore the efficacy of CDK4 inhibition using
palbociclib (
PD0332991), a highly selective inhibitor of CDK4/6, in a panel of
sarcoma cell lines and
sarcoma tumor xenografts (PDXs).
Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of CDK4
mRNA.
Palbociclib is also active in vivo against
sarcomas displaying high levels of CDK4 but not against
sarcomas displaying low levels of CDK4 and high levels of p16ink4a. The analysis of
tumors growing after
palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated
tumors. In summary, our data support the efficacy of CDK4 inhibitors against
sarcomas displaying increased CDK4 levels, particularly
fibrosarcomas and
MPNST. Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors.