| Project/Area Number |
18K15922
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Tanimoto Azusa 金沢大学, がん進展制御研究所, 助教 (90776444)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥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)
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| 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 |
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| 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.
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| 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。
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