Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, UPMC Hillman Cancer Center, and the Magee-Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Mol Cancer Ther. 2022 Sep 6;21(9):1473-1484. doi: 10.1158/1535-7163.MCT-21-0873.
Approximately 20% of high-grade serous ovarian cancers (HGSOC) have CCNE1 amplification. CCNE1-amplified tumors are homologous recombination (HR) proficient and resistant to standard therapies. Therapy resistance is associated with increased numbers of polyploid giant cancer cells (PGCC). We sought to identify new therapeutic approaches for patients with CCNE1-amplified tumors. Using TCGA data, we find that the mTOR, HR, and DNA checkpoint pathways are enriched in CCNE1-amplified ovarian cancers. Furthermore, Interactome Mapping Analysis linked the mTOR activity with upregulation of HR and DNA checkpoint pathways. Indeed, we find that mTOR inhibitors (mTORi) downregulate HR/checkpoint genes in CCNE1-amplified tumors. As CCNE1-amplified tumors are dependent on the HR pathway for viability, mTORi proved selectively effective in CCNE1-amplified tumors. Similarly, via downregulation of HR genes, mTORi increased CCNE1-amplifed HGSOC response to PARPi. In contrast, overexpression of HR/checkpoint proteins (RAD51 or ATR), induced resistance to mTORi. In vivo, mTORi alone potently reduced CCNE1-amplified tumor growth and the combination of mTORi and PARPi increased response and tumor eradication. Tumors treated with mTORi demonstrated a significant reduction in ALDH+ PGCCs. Finally, as a proof of principle, we identified three patients with CCNE1 amplified tumors who were treated with an mTORi. All three obtained clinical benefits from the therapy. Our studies and clinical experience indicate mTORi are a potential therapeutic approach for patients with CCNE1-amplified tumors.
大约 20%的高级别浆液性卵巢癌（HGSOC）存在 CCNE1 扩增。CCNE1 扩增的肿瘤同源重组（HR）功能正常，对标准治疗具有抗性。耐药性与多倍体巨癌细胞（PGCC）数量的增加有关。我们试图为 CCNE1 扩增的肿瘤患者寻找新的治疗方法。使用 TCGA 数据，我们发现 mTOR、HR 和 DNA 检查点途径在 CCNE1 扩增的卵巢癌中富集。此外，互作组图谱分析将 mTOR 活性与 HR 和 DNA 检查点途径的上调联系起来。事实上，我们发现 mTOR 抑制剂（mTORi）下调 CCNE1 扩增肿瘤中的 HR/检查点基因。由于 CCNE1 扩增的肿瘤依赖 HR 途径维持生存能力，mTORi 对 CCNE1 扩增的肿瘤具有选择性疗效。同样，通过下调 HR 基因，mTORi 增加了 CCNE1 扩增的 HGSOC 对 PARPi 的反应。相比之下，HR/检查点蛋白（RAD51 或 ATR）的过表达诱导对 mTORi 的耐药性。在体内，mTORi 单独就能强烈抑制 CCNE1 扩增肿瘤的生长，mTORi 和 PARPi 的联合使用增加了反应并消除了肿瘤。用 mTORi 治疗的肿瘤中，ALDH+PGCCs 显著减少。最后，作为一个原理证明，我们鉴定了三名接受 mTORi 治疗的 CCNE1 扩增肿瘤患者。所有三名患者都从治疗中获得了临床获益。我们的研究和临床经验表明，mTORi 是 CCNE1 扩增肿瘤患者的一种潜在治疗方法。
