CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest

• Published in: Molecular cancer therapeutics 2017-09, Vol.16 (9), p.1751-1764
• Main Authors: Francis, Ashleigh M, Alexander, Angela, Liu, Yanna, Vijayaraghavan, Smruthi, Low, Kwang Hui, Yang, Dong, Bui, Tuyen, Somaiah, Neeta, Ravi, Vinod, Keyomarsi, Khandan, Hunt, Kelly K
• Format: Article
• Language: English
• Subjects: Animals; Biological effects; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Proteins - antagonists & inhibitors; Cell Line, Tumor; Chemotherapy; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm - drug effects; Drugs; G1 phase; G2 phase; Gene Knockdown Techniques; Humans; Inhibitors; Male; Mice; Nuclear Proteins - antagonists & inhibitors; Patients; Piperazines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein-Tyrosine Kinases - antagonists & inhibitors; Pyrazoles - pharmacology; Pyridines - pharmacology; Pyrimidines - pharmacology; Pyrimidinones; Radiation; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Sarcoma; Sarcoma - drug therapy; Sarcoma - genetics; Sarcoma - metabolism; Sarcoma - pathology; Surgery; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-17-0040

Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5 cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G phase of the cell cycle, and upon drug removal cells progress through the cell cycle as expected within 6-24 hours. Using a long-term high-throughput assay that allows us to examine drugs in different sequences or concurrently, we found that palbociclib-induced cell-cycle arrest poises Rb-positive sarcoma cells (SK-LMS1 and HT-1080) to be more sensitive to agents that work preferentially in S-G phase such as doxorubicin and Wee1 kinase inhibitors (AZD1775). The synergy between palbociclib and AZD1775 was also validated using SK-LMS1 xenografts as well as Rb-positive patient-derived xenografts (PDX) developed from leiomyosarcoma patients. This work provides the necessary preclinical data in support of a clinical trial utilizing this treatment strategy. .