Identifying novel vulnerability of small cell lung carcinoma based on the mutually exclusive expression of master transcriptional regulators

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16139
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: Inoue Yusuke 浜松医科大学, 医学部附属病院, 助教 (10795470)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 形質制御転写因子 / 小細胞肺がん / 相互排他性 / 細胞分化 / ASCL1 / NEUROD1

Outline of Final Research Achievements

The molecular classification of small cell lung carcinoma (SCLC) based on the mutually exclusive expression patterns of lineage-related transcription factors (TFs) has been proposed. Here, we hypothesized that SCLC cells might undergo selection during evolution by cytotoxic effects of dual positivity of these TFs. In this study, the mutual exclusivity was most strongly observed between ASCL1 and NEUROD1 in clinical SCLC specimens. In addition, we found that co-expression of ASCL1 and NEUROD1 caused apoptosis in both ASCL1-driven and NEUROD1-driven SCLC cells. Further, the disruption of lineage-specific transcriptional programming was considered as the mechanism of cell death in our model. We are currently clarifying more detailed mechanisms behind the mutually exclusive expression of lineage-related TFs, eventually to identify novel druggable vulnerability of SCLC.

Free Research Field

肺がん、呼吸器内科学、腫瘍学

Academic Significance and Societal Importance of the Research Achievements

小細胞肺がんの病態には未解明な部分が多く、その治療には過去40年間で大きな進歩が見られていない。その結果、その予後は依然として極めて不良である。しかし、最近になり小細胞肺がんの遺伝子異常の他、その分化に関わる形質制御転写因子の存在が明らかにされてきた。
本研究は、この形質制御転写因子の発現が小細胞肺がんにおいて相互排他的に生じる機構の一つを説明しうるものであり、小細胞肺がんの病態生理の理解を深めるとともに、この相互排他性を標的とした小細胞肺がんのサブタイプ特異的な新たな治療戦略の確立の契機となる可能性を秘めていると考えられる。