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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 悪性黒色腫 / DUSP4 / DUSP6 / JUN / MAPK

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.

Free Research Field

実験病理

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。