Development of Novel Therapies Targeting Apoptosis Resistance Factors in ALK-rearranged Lung Cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K08516
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kanazawa University
• Principal Investigator: Takeuchi Shinji 金沢大学, 附属病院, 講師 (90565384)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: ALK肺がん / アポトーシス / STAT3

Outline of Final Research Achievements

Our study focused on developing novel therapeutic strategies targeting apoptosis resistance factors in ALK-rearranged lung cancer. Through functional genomic screening using small guide RNA libraries, we discovered that the treatment-induced adaptive survival of ALK-rearranged lung cancer cells is predominantly dependent on STAT3 activity following ALK inhibition. Inhibiting STAT3 significantly suppressed the adaptive survival of these cancer cells by enhancing ALK inhibition-induced apoptosis. In a xenograft study, the combination of YHO-1701 (a STAT3 inhibitor) and alectinib markedly suppressed tumor regrowth after treatment cessation, achieving near-complete tumor remission compared to alectinib alone. These findings provide new insights into the development of combined therapeutic strategies targeting apoptosis resistance factors in patients with ALK-rearranged lung cancer.

Free Research Field

腫瘍内科

Academic Significance and Societal Importance of the Research Achievements

ALK融合遺伝子陽性の肺がん（ALK肺がん）患者にALKチロシンキナーゼ阻害薬（ALK-TKI）は奏効するが、ほとんどの場合、腫瘍は残存してがん細胞が生存し、数年の経過で多様な耐性を獲得して増悪するため、耐性後の治療が困難である。本研究では、ALK-TKI投与下でALK肺がん細胞が生存する機構を見出し、STAT3に対する選択的阻害薬の併用によりALK肺がん細胞をほぼ死滅させられることを実験的に明らかにした。臨床試験での検討が必要であるが、肺がん患者の予後改善に寄与できる可能性がある。