Elucidation and overcoming the drug tolerant mechanism in ALK-rearranged lung cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22820
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tanimura Keiko 京都府立医科大学, 医学(系)研究科(研究院), 研修員 (10768807)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: ALK / 肺がん / 治療抵抗性 / HER3 / 間葉上皮転換 / alectinib / vimentin

Outline of Final Research Achievements

ALK inhibitors have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, survived drug-tolerant cells will develop to tumor recurrence. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK inhibitor alone, cotreatment with pan-HER inhibitor afatinib and ALK inhibitor prevented tumor regrowth via suppression of HER3 signaling, leading to the eradication of tumors in ALK-rearranged tumor with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor outcomes in alectinib treatment.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

ドライバー遺伝子異常に起因する肺がんに対しては、がん分子標的治療薬が高い治療効果を示す。しかし治療を継続することにより耐性を獲得するため、耐性克服は重要な課題の一つである。耐性化後の治療介入が困難である背景から、分子標的治療薬の初期治療抵抗性に対する治療を行うことで、耐性獲得を予防するというアプローチが、肺がん患者の予後のさらなる改善に繋がる新たな治療戦略になる可能性を秘めている。本研究では、ALK肺がんの中でもALK阻害薬への感受性が低い集団に対し、HER3阻害による治療抵抗性克服の可能性を見出しており、臨床的意義は高いと考えられる。