Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
Cell, Developmental & Cancer, Oregon Health & Science University, Portland, Oregon, 97239, USA.
J Hematol Oncol. 2017 Nov 13;10(1):173. doi: 10.1186/s13045-017-0540-x.
Liposarcoma, the most common soft tissue tumor, is understudied cancer, and limited progress has been made in the treatment of metastatic disease. The Achilles heel of cancer often is their kinases that are excellent therapeutic targets. However, very limited knowledge exists of therapeutic critical kinase targets in liposarcoma that could be potentially used in disease management.
Large RNAi and small-molecule tyrosine kinase inhibitor screens were performed against the proliferative capacity of liposarcoma cell lines of different subtypes. Each small molecule inhibitor was either FDA approved or in a clinical trial.
Screening assays identified several previously unrecognized targets including PTK2 and KIT in liposarcoma. We also observed that ponatinib, multi-targeted tyrosine kinase inhibitor, was the most effective drug with anti-growth effects against all cell lines. In vitro assays showed that ponatinib inhibited the clonogenic proliferation of liposarcoma, and this anti-growth effect was associated with apoptosis and cell cycle arrest at the G0/G1 phase as well as a decrease in the KIT signaling pathway. In addition, ponatinib inhibited in vivo growth of liposarcoma in a xenograft model.
Two large-scale kinase screenings identified novel liposarcoma targets and a FDA-approved inhibitor, ponatinib with clear anti-liposarcoma activity highlighting its potential therapy for treatment of this deadly tumor.
脂肪肉瘤是最常见的软组织肿瘤，其相关研究较少，转移性疾病的治疗也鲜有进展。癌症的弱点通常是它们的激酶，激酶是极好的治疗靶点。然而，对于脂肪肉瘤中潜在的可用于疾病管理的治疗关键激酶靶点，我们知之甚少。
针对不同亚型的脂肪肉瘤细胞系的增殖能力，进行了大规模的 RNAi 和小分子酪氨酸激酶抑制剂筛选。每种小分子抑制剂要么已获得 FDA 批准，要么正在临床试验中。
筛选实验鉴定出了一些以前未被识别的靶点，包括脂肪肉瘤中的 PTK2 和 KIT。我们还观察到，多靶点酪氨酸激酶抑制剂帕纳替尼是最有效的药物，对所有细胞系均具有抗增殖作用。体外实验表明，帕纳替尼抑制脂肪肉瘤的集落形成增殖，这种抗生长作用与细胞凋亡和细胞周期阻滞在 G0/G1 期以及 KIT 信号通路的减少有关。此外，帕纳替尼还抑制了异种移植模型中脂肪肉瘤的体内生长。
两项大规模的激酶筛选鉴定出了新的脂肪肉瘤靶点和一种 FDA 批准的抑制剂——帕纳替尼，其具有明确的抗脂肪肉瘤活性，突出了其在治疗这种致命肿瘤方面的潜在治疗价值。
