Department of Gynecologic Oncology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Clin Cancer Res. 2018 Aug 15;24(16):3928-3940. doi: 10.1158/1078-0432.CCR-17-3060. Epub 2018 Apr 23.
Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor and activating mutations in the PI3K subunit In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models. In a large set of patients with OCCC ( = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines ( = 17) and OCCC patient-derived xenografts ( = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055. We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient-derived xenograft models. These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. .
晚期卵巢透明细胞癌（OCCC）对常规铂类化疗无反应。OCCC 的常见改变包括肿瘤抑制因子的有害突变和 PI3K 亚基的激活突变。在这项研究中，我们旨在鉴定 OCCC 患者中目前未知的突变激酶，并在 OCCC 模型中测试下游受影响途径的药物可及性。在一组较大的 OCCC 患者（n=124）中，对人类激酶组（518 个激酶）和其他癌症相关基因进行了测序，并确定了拷贝数改变。使用遗传特征明确的 OCCC 细胞系（n=17）和 OCCC 患者来源的异种移植瘤（n=3），对 ERBB 酪氨酸激酶抑制剂厄洛替尼和拉帕替尼、PARP 抑制剂奥拉帕利以及 mTORC1/2 抑制剂 AZD8055 进行了药物测试。我们鉴定出了一些在激酶中低频出现的假定驱动突变，这些突变以前在 OCCC 中没有被注释过。结合突变和拷贝数改变，所有肿瘤中有 91%受到 PI3K/AKT/mTOR 通路、MAPK 通路或 ERBB 家族受体酪氨酸激酶的影响，82%受到 DNA 修复通路的影响。OCCC 患者中强烈的 p-S6 染色表明 mTORC1/2 活性较高。我们一致发现，大多数 OCCC 细胞系对 AZD8055 抑制 mTORC1/2 特别敏感，而对靶向 ERBB 家族受体酪氨酸激酶或 DNA 修复信号的药物不敏感。随后，我们在所有独特的 OCCC 患者来源异种移植瘤模型中证明了 mTORC1/2 抑制的疗效。这些结果表明 mTORC1/2 抑制是 OCCC 的一种有效治疗策略。
