Investigation of the molecular mechanism mediating the acquired resistance to docetaxel in castration-resistant prostate cancer and the development of the novel therapy targeting this mechanism

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K09164
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: MIYAKE Hideaki 浜松医科大学, 医学部, 教授 (60379435)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 去勢抵抗性前立腺癌 / ドセタキセル / 耐性獲得機構 / 新規治療

Outline of Final Research Achievements

A parental human CRPC cell line, PC3 (PC3/P) was continuously exposed to increasing doses of docetaxel, and cell line resistant to docetaxel, PC3/R, was developed. There were no significant differences in sensitivities to cabazitaxel, between PC3/P and PC3/R. In PC3/P, both docetaxel and cabazitaxel markedly inhibited the expression levels of phosphorylated Akt and p44/42 MAPK. In PC3/R, however, phosphorylation of Akt and p44/42 MAPK were maintained following treatment with docetaxel, whereas treatment with cabazitaxel resulted in the marked down-regulation of phosphorylated Akt, but not that of p44/42 MAPK. Antitumor activity of cabazitaxel in CRPC cells even after the acquisition of resistance to docetaxel could be explained, at least in part, by the inactivation of Akt, persistently phosphorylated following treatment with docetaxel.

Free Research Field

泌尿器科悪性腫瘍

Academic Significance and Societal Importance of the Research Achievements

ドセタキセルはホルモン療法に抵抗性を獲得した進行前立腺癌に対する第一選択の治療である。本研究ではドセタキセル抵抗性前立腺癌株を樹立し、その解析を行ったところ，ドセタキセル抵抗性にAktの恒常的リン酸化が重要な役割を果たしていることを明らかにし，Akt特異的阻害剤がドセタキセル抵抗性前立腺癌株のドセタキセルに対する感受性を顕著に亢進させることを示した。以上より、上記の試みが進行前立腺癌に対する新たな治療戦略になりえる可能性があると考える。