MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer
Autor: | Hailing Cheng, Yijue Xue, Fuwen Luo, Kui Jiang, Pixu Liu, Lanlin Shen, Yaxun Jia, Xiaolin Sang, Chongya Liu, Zhiwei Tao, Min Wang, Jingyan Yi |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Research paper Cell Survival Pyridines Genes myc Antineoplastic Agents Synthetic lethality Poly(ADP-ribose) Polymerase Inhibitors Palbociclib Genomic Instability Piperazines General Biochemistry Genetics and Molecular Biology Olaparib Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Cell Line Tumor Animals Humans Medicine RNA Small Interfering Ovarian Neoplasms business.industry Cancer Drug Synergism General Medicine medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Disease Models Animal 030104 developmental biology chemistry 030220 oncology & carcinogenesis PARP inhibitor Cancer research Phthalazines Female business Ovarian cancer DNA Damage Signal Transduction Combination drug |
Zdroj: | EBioMedicine. 43:225-237 |
ISSN: | 2352-3964 |
Popis: | Background While PARP inhibitors and CDK4/6 inhibitors, the two classes of FDA-approved agents, have shown promising clinical benefits, there is an urgent need to develop new therapeutic strategies to improve clinical response. Meanwhile, extending the utility of these inhibitors beyond their respective molecularly defined cancer types is challenging and will likely require biomarkers predictive of treatment response especially when used in a combination drug development setting. Methods The effects of PARP inhibitor Olaparib and CDK4/6 inhibitor Palbociclib on ovarian cancer cells lines including those of high-grade serous histology were examined in vitro and in vivo. We investigated the molecular mechanism underlying the synergistic effects of drug combination. Findings We show for the first time that combining PARP and CDK4/6 inhibition has synergistic effects against MYC overexpressing ovarian cancer cells both in vitro and in vivo. Mechanistically, we find that Palbociclib induces homologous recombination (HR) deficiency through downregulation of MYC-regulated HR pathway genes, causing synthetic lethality with Olaparib. We further demonstrate that MYC expression determines sensitivity to combinatorial treatment with Olaparib and Palbociclib. Interpretation Our data provide a rationale for clinical evaluation of therapeutic synergy of these two classes of inhibitors in ovarian cancer patients whose tumors show high MYC expression and who do not respond to PARP inhibitors or CDK4/6 inhibitors monotherapies. Fund This work was supported by the National Natural Science Foundation of China [81672575, 81874111, 81472447 to HC; 81572586 and 81372853 to PL], and the Liaoning Provincial Key Basic Research Program for Universities [LZ2017002 to HC]. |
Databáze: | OpenAIRE |
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