Research on signal transduction inhibitors and novel molecules with synthetic lethal effects in melanoma

Research Project

Project/Area Number	20K07377
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Review Section	Basic Section 49020:Human pathology-related
Research Institution	Iwate Medical University
Principal Investigator	Maesawa Chihaya 岩手医科大学, 医歯薬総合研究所, 教授 (10326647)
Co-Investigator(Kenkyū-buntansha)	安平進士岩手医科大学, 医歯薬総合研究所, 講師 (90311729)
Project Period (FY)	2020-04-01 – 2023-03-31
Project Status	Completed (Fiscal Year 2022)
Budget Amount *help	¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000) Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000) Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords	悪性黒色腫 / DUSP4 / DUSP6 / JUN / MAPK / BRAF-MAPK / BRAF / MITF
Outline of Research at the Start	悪性黒色腫の治療成績改善には、ドライバー経路に作用するBRAF/MEK阻害薬の効果延長が命題となっている。本研究では、悪性黒色腫のドライバー経路と補完関係にあり、合成致死をもたらすパートナー分子を特定し、シグナル伝達阻害薬の効果増強/耐性の克服法を開発する．DUSP4/JNK、ならびにMITF/BCL2 、②オートファジー阻害経路に関して研究し、悪性黒色腫治療のプラットフォームの作成に寄与する。
Outline of Final Research Achievements	We aim to identify partner molecules that have a complementary relationship with the driver pathway of malignant melanoma and have the potential to cause synthetic lethality, and to develop methods to enhance the effects of signal transduction inhibitors or overcome resistance. We conducted analyses on the pathway of apoptosis induction through USP4 inhibition, resulting in JNK activation and suppression of MITF/BCL2 family expression, as well as the pathway of inhibition of survival-promoting autophagy. Database research revealed a prominent survival dependency on DUSP4 in malignant melanoma. The depletion of DUSP4 reduced the phosphorylation of ERK1/2, but it did not affect the phosphorylation of c-Jun kinase. The disruption of DUSP4 resulted in an increase in DUSP6 levels via a post-transcriptional process, demonstrating that DUSP4 plays a role in maintaining ERK1/2 activity by negatively regulating DUSP6. DUSP4/6 was considered as a novel therapeutic target for malignant melanoma.
Academic Significance and Societal Importance of the Research Achievements	本研究では、従前の他がん種の報告で見過ごされてきた、悪性黒色腫特異的な生存機構に着目した点で、独自性・独創性がある。本研究の成果は、未だ治療法の確立していない半数の進行悪性黒色腫患者の新規治療法の開発につながる視点を持った意義のある研究である。