Cancer Institute, The Second Hospital of Dalian Medical University, Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China.
Department of Oncology, The Second Hospital of Dalian Medical University, Dalian 116044, China.
EBioMedicine. 2019 May;43:225-237. doi: 10.1016/j.ebiom.2019.03.027. Epub 2019 Mar 18.
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.
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.
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.
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].
PARP 抑制剂和 CDK4/6 抑制剂是两种已获 FDA 批准的药物类别，它们已显示出有前景的临床获益，但仍迫切需要开发新的治疗策略以提高临床反应。同时，将这些抑制剂的用途扩展到各自的分子定义的癌症类型之外是具有挑战性的，当在联合药物开发环境中使用时，尤其需要预测治疗反应的生物标志物。
我们在体外和体内研究了 PARP 抑制剂奥拉帕尼和 CDK4/6 抑制剂哌柏西利对卵巢癌细胞系（包括高级别浆液性组织学的细胞系）的影响。我们研究了药物联合使用的协同作用的分子机制。
我们首次表明，PARP 和 CDK4/6 抑制联合使用对 MYC 过表达的卵巢癌细胞具有协同作用，无论是在体外还是在体内。从机制上讲，我们发现哌柏西利通过下调 MYC 调控的 HR 通路基因导致同源重组 (HR) 缺陷，从而与奥拉帕尼产生合成致死性。我们进一步证明，MYC 表达决定了对奥拉帕尼和哌柏西利联合治疗的敏感性。
我们的数据为这些两种抑制剂在卵巢癌患者中的临床评估提供了依据，这些患者的肿瘤具有高 MYC 表达，且对 PARP 抑制剂或 CDK4/6 抑制剂单药治疗无反应。
这项工作得到了中国国家自然科学基金 [81672575、81874111、81472447 资助（HC）；81572586 和 81372853 资助（PL）]和辽宁省重点基础研究计划（HC）的支持。
