Elucidation of the mechanism of resistance to apoptosis in ALK rearranged NSCLC

• Project/Area Number: 18K15922
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kanazawa University
• Principal Investigator: Tanimoto Azusa 金沢大学, がん進展制御研究所, 助教 (90776444)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: ALK / Mcl-1 / Noxa / Proteasome / p53 / アポトーシス / ALK融合遺伝子陽性肺癌 / 自然耐性 / ALK阻害薬 / 肺癌 / ALK融合遺伝子 / 分子標的薬 / PUMA

Outline of Final Research Achievements

We used integrated clinical and next-generation sequencing data. ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs.In 90 ALK-rearranged NSCLC patients who were treated with a selective ALK-TKI, alectinib, TP53 co-mutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months vs.NR; p=0.0008; hazard ratio, 0.33]. ALK-rearranged NSCLC cell lines which lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazommib markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a pro-apoptotic protein, Noxa which bound to an anti-apoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from ALK-rearranged NSCLC cells with non-functional p53.

Academic Significance and Societal Importance of the Research Achievements

ALK融合遺伝子陽性肺癌の約1/4にTP53変異が共存しており、本来有効であるALK阻害薬の効果を減弱させる要因となっていることが明らかにした。TP53変異はEGFR遺伝子などの他のドライバー遺伝子変異陽性肺癌にも共存しており、本研究は選択的Mcl-1阻害薬の開発の意義が高めた。

Research Products

• [Journal Article] Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression (2020)
  • Author(s): Tanimoto Azusa、Matsumoto Shingo、Takeuchi Shinji、Arai Sachiko、Fukuda Koji、Nishiyama Akihiro、Yoh Kiyotaka、Ikeda Takaya、Furuya Naoki、Nishino Kazumi、Ohe Yuichiro、Goto Koichi、Yano Seiji
  • Journal Title: Clinical Cancer Research Volume: 27 Issue: 5 Pages: 1410-1420
  • DOI: 10.1158/1078-0432.ccr-20-2853
  • Peer Reviewed / Open Access
• [Presentation] ALK融合遺伝子陽性肺癌におけるp53の機能低下に起因するALK阻害薬耐性の新規克服治療の開発 (2020)
  • Author(s): 谷本 梓
  • Organizer: 第86回日本呼吸器学会北陸地方会
• [Presentation] ALK 融合遺伝子陽性肺癌においてp53 の機能低下がもたらすALK-TKI 自然耐性の克服 (2019)
  • Author(s): 谷本 梓
  • Organizer: 第60回日本肺癌学会学術集会
• [Presentation] Proteasome inhibitor overcomes ALK-TKI resistance by p53 inactivation through Noxaexpression in EML4-ALK NSCLC (2019)
  • Author(s): 谷本 梓
  • Organizer: 第17回日本臨床腫瘍学会学術集会
• [Presentation] 分子標的薬の自然耐性に着目した基礎研究と臨床応用への試み (2019)
  • Author(s): 谷本 梓
  • Organizer: 第13回日本緩和医療薬学会年会
  • Invited