MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancerResearch in context
Jingyan Yi,
Chongya Liu,
Zhiwei Tao,
Min Wang,
Yaxun Jia,
Xiaolin Sang,
Lanlin Shen,
Yijue Xue,
Kui Jiang,
Fuwen Luo,
Pixu Liu,
Hailing Cheng
Affiliations
Jingyan Yi
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Chongya Liu
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Zhiwei Tao
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Min Wang
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Yaxun Jia
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Xiaolin Sang
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Lanlin Shen
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Yijue Xue
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China
Kui Jiang
Department of Oncology, The Second Hospital of Dalian Medical University, Dalian 116044, China
Fuwen Luo
Department of Acute Abdomen Surgery, The Second Hospital of Dalian Medical University, Dalian 116044, China
Pixu Liu
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China; College of Pharmacy, Dalian Medical University, Dalian 116044, China; Corresponding author at: Institute of Cancer Stem Cell, College of Pharmacy, Dalian Medical University, Dalian, Liaoning, China
Hailing Cheng
Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China; Corresponding author at: Cancer Institute, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
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]. Keywords: MYC, PARP inhibitor, CDK4/6 inhibitor, HR repair, Ovarian cancer
