Abstract
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.
Highlights
Sarcomas are malignant tumors derived from the mesenchymal nonepithelial tissue developed from the embryonic mesoderm [1], comprising less than 10% of all cancers [2, 3] but account for a higher percentage of overall cancer morbidity and mortality in children and young adults than in adults
Palbociclib induces senescence in sarcoma cell lines from different origins To explore the effect of CDK4 inhibition, we used a panel of 10 low-passaged sarcoma cell lines generated directly from patient samples and 2 commercial cell lines of heterogeneous origin and different molecular karyotypes (Table 1) [53, 54, 57]
To study the effect of CDK4 inhibition in sarcoma, a tumor type with few therapeutic approaches, we examined the effects of the CDK4 inhibitor palbociclib on sarcoma cell lines and patient-derived xenografts (PDXs) models
Summary
Sarcomas are malignant tumors derived from the mesenchymal nonepithelial tissue developed from the embryonic mesoderm [1], comprising less than 10% of all cancers [2, 3] but account for a higher percentage of overall cancer morbidity and mortality in children and young adults than in adults. Taxonomical analysis of sarcomas has identified approximately 60 subtypes of sarcoma, as well as more than 50 benign tumor subtypes [4]. Sarcomas are usually grouped in two broad categories according to molecular genetics: sarcomas harboring a diploid or nearly diploid karyotype and simple genetic driver alterations, such as Ewing’s sarcoma, or sarcomas with a complex and imbalanced karyotype, such as osteosarcoma. Both subgroups include very different clinical entities and are broadly drawn, not reflecting the genetic diversity among tumors of a given type or subtype or their diverse tumor biology [4]
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