HER2 intratumoral heterogeneity and drug resistance to trastsuzumab in early gastric cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16593
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Suzuka University of Medical Science
• Principal Investigator: Kanayama Kazuki 鈴鹿医療科学大学, 保健衛生学部, 准教授 (20605943)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: HER2 / 腫瘍内不均一性 / 早期胃癌 / トラスツズマブ / 治療抵抗性

Outline of Final Research Achievements

In HER2 heterogeneous gastric cancer, we speculate that subclones harboring driver or treatment-resistant mutations other than HER2 gene amplification arise at an early stage, leading to the formation of HER2-independent pathways and the acquisition of trastuzumab treatment resistance. In this study, we performed a comprehensive mutational analysis of cancer-related genes in HER2 heterogeneous early gastric cancer with the aim of identifying the existence of subclones involved in these genes. Comprehensive mutation analysis revealed gain-of-function mutations such as PIK3CA from HER2 heterogeneous early gastric cancer. This suggests that subclones with driver mutations other than HER2 gene amplification appear at an early stage in HER2 heterogeneous gastric cancer.

Free Research Field

人体病理学

Academic Significance and Societal Importance of the Research Achievements

トラスツズマブ療法はHER2陽性胃癌の重要な治療選択の一つであるが、HER2不均一性胃癌では治療抵抗性を示すことから、多くの患者が治療の恩恵を受けるためにもトラスツズマブ治療抵抗性を引き起こす分子メカニズムの解明が重要となる。本研究成果において腫瘍内のゲノム進化の一部が解明され、HER2不均一性胃癌では癌の早期段階でHER2遺伝子増幅と併存するドライバー変異や腫瘍全体で共通するドライバー変異の存在が明らかとなった。これにより、HER2非依存性経路を同時に遮断する治療法やドライバー変異を標的とした新規治療法の開発に繋がる可能性があることを示した。