BIG3-PHB2 complexes is required for the acquired trastuzumab-resistance of HER2-positive breast cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08958
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: The University of Tokushima
• Principal Investigator: YOSHIMARU Tetsuro 徳島大学, 先端酵素学研究所, 准教授 (80424729)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: HER2陽性乳がん / BIG3-PHB2複合体 / トラスツズマブ耐性 / ペプチド創薬 / ステープル化ペプチド / がん抑制因子

Outline of Final Research Achievements

Anti-HER2 antibody, trastuzumab, has greatly improved outcomes of patients with HER2-positive breast cancer, but the resistance acquisition remains a severe problem. We previously demonstrated that a cancer-specific scaffold protein BIG3 plays critical roles for HER2-signaling activation by inactivating tumor-suppressor prohibitin 2 (PHB2). Here we report the physiological significance of the BIG3-PHB2 complex in acquired trastuzumab-resistant breast cancers. Notably, BIG3-PHB2 complexes are transported to the plasma membrane from the trans-Golgi network of trastuzumab-resistant cells, contributing to the HER2-EGFR formation involved in trastuzumab-resistance. More importantly, treatment with peptide inhibitor targeting the BIG3-PHB2 interaction led to the remarkable inhibition of HER2-EGFR hetero dimerization, resulting in suppression of trastuzumab-resistant cell proliferation. These findings suggest that the BIG3-PHB2 complex is pivotal in acquiring trastuzumab-resistance.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

BIG3-PHB2複合体が乳がんをはじめとするがん細胞に特異的に発現していることに起因しており、BIG3-PHB2複合体の標的ペプチドstERAPは正常組織にダメージを与えることなく、がん組織特異的に作用できるため、重篤な副作用を回避できる。さらに、このペプチドは長期持続薬効を示すことから、繰り返す再発や転移による治療困難な難治性乳がん患者に対する長期的に有効な治療法となり、身体的負担の軽減によるインパクトなど多大な社会的貢献は大きい。