2022 Fiscal Year Final Research Report
Overcoming drug-induced interstital lung disease caused by molecular targeted therapy in lung cancer
| Project/Area Number |
20K08555
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Hyogo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
木島 貴志 兵庫医科大学, 医学部, 教授 (90372614)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | ドライバー遺伝子変異・転座陽性肺癌 / 薬剤性間質性肺炎 / Hippoシグナル伝達系 / 腫瘍関連マクロファージ |
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| Outline of Final Research Achievements |
Recent molecular-targeted therapy brought about dramatic improvement in the outcome of the patients with lung cancer. On the other hand, those molecular-targeted therapy sometimes causes fatal drug-induced interstitial lung disease (ILD). We focused on the interaction between lung cancer cells and tumor-associated macrophages (TAMs) which are one of the major components of tumor microenvironment. Small molecule inhibitors such as epidermal growth factor receptor tyrosine kinase inhibitor and anaplastic lymphoma kinase inhibitor exert dramatic antitumor activity and can induce senescence in large number of lung cancer cells. Senescent cells release abundant senescence-associated secretory phenotype (SASP). These SASP are supposed to be associated with activation of TAMs, which cause ILD via inducing both inflammation and fibrosis. We considered that regulation of transcriptional co-activators YAP and TAZ could reduce the occurrence of ILD via suppressing the production of SASP.
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| Free Research Field |
呼吸器悪性腫瘍
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| Academic Significance and Societal Importance of the Research Achievements |
ドライバー遺伝子変異を標的とした小分子阻害薬や免疫チェックポイント阻害薬（ICI）の登場で、肺癌の予後は確実に改善している。その一方で、約5%の症例では小分子阻害剤やICIによる重篤な薬剤性肺障害を発症してしまう。また、もともと間質性肺炎を合併した肺癌症例では、内科的治療が主となる事が多いにも関わらず、やはり急性増悪のリスクから安全に使用できる薬剤が少なく、治療選択肢が極めて限られている。本研究でYAP/TAZの制御により、小分子阻害薬やICIによる薬剤性肺障害のリスクを低減できれば、現行治療がより安全にできるだけでなく、これらの薬剤が不適格とされていた症例にも適応を拡大できる可能性がある。
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