Sequential Combination Therapy of CDK Inhibition and Doxorubicin Is Synthetically Lethal in p53-Mutant Triple-Negative Breast Cancer

• Published in: Molecular cancer therapeutics 2016-04, Vol.15 (4), p.593-607
• Main Authors: Jabbour-Leung, Natalie A, Chen, Xian, Bui, Tuyen, Jiang, Yufeng, Yang, Dong, Vijayaraghavan, Smruthi, McArthur, Mark J, Hunt, Kelly K, Keyomarsi, Khandan
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - genetics; Cell Line, Tumor; Cyclin-Dependent Kinases - antagonists & inhibitors; Disease Models, Animal; DNA Breaks, Double-Stranded; DNA Damage; DNA Repair; Doxorubicin - pharmacology; Drug Synergism; Drug Therapy, Combination; Female; G1 Phase Cell Cycle Checkpoints - drug effects; G1 Phase Cell Cycle Checkpoints - genetics; Gene Deletion; Humans; Mice; Protein Kinase Inhibitors - pharmacology; Synthetic Lethal Mutations; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Tumor Suppressor Protein p53 - genetics; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-15-0519

Triple-negative breast cancer (TNBC) is an aggressive malignancy in which the tumors lack expression of estrogen receptor, progesterone receptor, and HER2. Hence, TNBC patients cannot benefit from clinically available targeted therapies and rely on chemotherapy and surgery for treatment. While initially responding to chemotherapy, TNBC patients are at increased risk of developing distant metastasis and have decreased overall survival compared with non-TNBC patients. A majority of TNBC tumors carry p53 mutations, enabling them to bypass the G1 checkpoint and complete the cell cycle even in the presence of DNA damage. Therefore, we hypothesized that TNBC cells are sensitive to cell-cycle-targeted combination therapy, which leaves nontransformed cells unharmed. Our findings demonstrate that sequential administration of the pan-CDK inhibitor roscovitine before doxorubicin treatment is synthetically lethal explicitly in TNBC cells. Roscovitine treatment arrests TNBC cells in the G2-M cell-cycle phase, priming them for DNA damage. Combination treatment increased frequency of DNA double-strand breaks, while simultaneously reducing recruitment of homologous recombination proteins compared with doxorubicin treatment alone. Furthermore, this combination therapy significantly reduced tumor volume and increased overall survival compared with single drug or concomitant treatment in xenograft studies. Examination of isogenic immortalized human mammary epithelial cells and isogenic tumor cell lines found that abolishment of the p53 pathway is required for combination-induced cytotoxicity, making p53 a putative predictor of response to therapy. By exploiting the specific biologic and molecular characteristics of TNBC tumors, this innovative therapy can greatly impact the treatment and care of TNBC patients. Mol Cancer Ther; 15(4); 593-607. ©2016 AACR.