Effects of novel anti-ASCT2 monoclonal antibody on human tumor harboring KRAS mutation

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16876
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kindai University
• Principal Investigator: Hara Yuta 近畿大学, 薬学部, 助教 (20803779)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: ASCT2 / KRAS / 大腸癌 / モノクローナル抗体

Outline of Final Research Achievements

Mutations in KRAS are detected in various human cancers. However, there are few effective drugs for KRAS-mutated cancers. Glutamine is thought to be one of the pivotal nutrients for proliferation and survival of cancer cells. ASCT2 (SLC1A5) is a multi-pass transmembrane protein that transports neutral amino acids. ASCT2 is reported to be highly expressed in many cancer cells, and is thought to work as a major transporter for glutamine. We have developed a novel monoclonal antibody (mAb) against the extracellular domain of human ASCT2. In the present study, we examined the effects of the mAb on KRAS-mutated colorectal cancer cells. Treatment with anti-ASCT2 mAb decreased the concentration of intracellular glutamine and in vivo tumor growth. However, these effects were not observed in colorectal cancer cells which harbor wild-type KRAS. These results suggest that ASCT2 is a promising therapeutic target for KRAS-mutated cancers.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

KRAS遺伝子は、多くのがんで変異が認められる。分子標的治療薬の登場により、がん治療は格段に進歩したが、未だKRAS遺伝子に変異のあるがんに対しては治療法が存在しない。また、KRAS遺伝子が変異した大腸癌以外のがん種においても、その生存・増殖がグルタミン代謝に非常に強く依存していることが知られている。したがって、本研究で見出したASCT2の阻害によるグルタミン取込みの抑制がKRAS遺伝子変異の大腸癌の増殖を阻害するという知見は、KRAS遺伝子に変異のある様々ながん種に対する治療戦略の開発に貢献出来ると考えている。