Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16417
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Osaka University
• Principal Investigator: Ishida Tomo 大阪大学, 大学院医学系研究科, 招へい教員 (60804052)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: GIST / 遺残細胞 / フェロトーシス / 分子標的治療

Outline of Final Research Achievements

Despite the effectiveness of tyrosine kinase inhibitors (TKI), GIST develop after the withdrawal of TKI. Based on previous studies, a subpopulation of drug-tolerant cells called persister cells may be responsible for the recurrence.The metabolic changes were investigated in imatinib-derived persister GIST cells. We investigated the efficacy and the mechanism of GPX4 inhibitor, which is known as a major inducer of ferroptosis.
We demonstrated a downregulation of glucose metabolism, subsequent decrease in the glutathione level and sensitivity to glutathione peroxidase 4 (GPX4) inhibitor, RSL3 in persister cells. As the cell death induced by RSL3 was found to be irondependen and caspase-independent, loss of GPX4 function could have possibly induced selective persister cell ferroptotic death. In the xenograft model, we confirmed the inhibition of tumour regrowth after discontinuation of imatinib treatment.
RSL3 combined with TKI may be a promising therapy for GIST.

Free Research Field

腫瘍学

Academic Significance and Societal Importance of the Research Achievements

化学療法後の遺残細胞に関しては肺癌・乳癌・皮膚癌などで報告があるが、いずれも「分子標的治療薬投与後」の遺残細胞に共通する現象として捉えられている。GISTは、固形腫瘍における分子標的治療の成功モデルケースであり、その耐性メカニズムの解明は、GISTのみならず肺がん、血液がん、大腸がん等で、分子標的治療薬が用いられるすべての疾患の耐性の解明につながると考えられ非常に大きな意義があると考えられる。
さらには、本治療が臨床応用されることで、中止不可能とされているGISTにおけるチロシンキナーゼ阻害剤が有効中止の可能性ができ社会的にも価値が高いと考えられる。