Elucidation of the resistance mechanism to the molecular targeting drug in renal cancer using the genome editing technology

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16799
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Kagoshima University
• Principal Investigator: YONEMORI Masaya 鹿児島大学, 附属病院, 医員 (00758013)
• Research Collaborator: Nakagawa Masayuki ; Enokida Hideki ; Yoshino Hirofumi ; Gutkind JS ; Nohata Nijiro ; Sugita Satoshi ; Sakaguchi Satoshi
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 腎癌 / CRISPR/Cas9 / PHGDH / 低酸素誘導因子

Outline of Final Research Achievements

We established a sunitinib-resistant RCC cell line, followed by the establishment of HIF2α knockout cell line (HIF2α-KO-SU-R-786-o) by CRISPR/Cas9. By using omics analyses using the cell, we found that serine biosynthesis was significantly activated in HIF2α-KO-SU-R-786-o, and that PHGDH, a key enzyme for serine synthesis, was accelerated in HIF2α-KO-SU-R-786-o. PHGDH inhibitor reduced cell growth in vivo and in vitro by inducing apoptosis in HIF2α-KO-SU-R-786-o more than in parent cells. Public database showed that patients with PHGDH gene amplification had poor overall survival (P = 0.0003) compared to patients without amplification. In conclusion, PHGDH can be a therapeutic target for patients showing activated serine biosynthesis after HIF2α deficiency. Furthermore, PHGDH inhibitor should be considered as a first treatment in patients with PHGDH amplification.

Free Research Field

Urological cancer

Academic Significance and Societal Importance of the Research Achievements

転移性腎癌の多くは分子標的治療薬に治療抵抗性を獲得し、再発・転移に至るが、低酸素誘導因子(HIF) の恒常的な活性化は腎癌の進展のみでなく、腎癌治療に一時治療として使用されているmTOR阻害剤や血管新生阻害剤の耐性獲得にも重要な役割を果たすとされている。本研究では、CRISPR/Cas9によるゲノム編集技術を用いて当科で作成したスニチニブ(マルチキナーゼ阻害剤)耐性HIFノックアウト腎癌細胞株を使用して、腎癌の増殖・浸潤・転移および薬剤耐性に関わる癌シグナル経路を解明することが出来た。本研究の成果により、転移性腎癌に対する新たな治療戦略の可能性が提案された。