Research

Life Sciences & Biotechnology

Title :

Investigating oncogenic mutations and regulatory mechanisms of HER2 to devise an alternative strategy for HER2-directed therapies in breast cancer

Area of research :

Life Sciences & Biotechnology

Principal Investigator :

Dr. Kakoli Bose, Tata Memorial Centre (Hospital), Maharashtra

Timeline Start Year :

2022

Timeline End Year :

2025

Contact info :

Equipments :

Details

Executive Summary :

Breast cancer is a prevalent cancer in females in India and globally, with human epidermal growth factor receptor 2 (HER2) being overexpressed in around 20% of cases. This overexpression leads to the activation of downstream proliferation and survival pathways, often resulting in malignant phenotypes. Anti-HER2 monoclonal antibodies like trastuzumab and pertuzumab remain ineffective due to their high expression level. Drug resistance and side-effects in both antibody-based and tyrosine kinase inhibitor-based therapies further challenge the need for alternative therapeutic approaches. Her2 modulates its kinase activity allosterically through homo- (HER2-HER2) and HER3 mediated hetero-dimerization (HER2-HER3), triggering conformational changes in the protein. However, a significant gap in understanding allosteric regulation of HER2 receptor tyrosine kinase (RTK) activity from structural and quantitative biophysical perspectives has limited its applicability in translational endeavors. This study aims to bridge this gap by understanding the driving force that defines homo-/heterodimerization equilibrium and protein-protein interactions of HER2 and its variants with HER3 using structural and biophysical probes. This will help delineate the key regulatory switch driving HER2 toward dimerization and highlight the structural changes at the backdrop of breast-cancer associated ECD mutations. This knowledge will enable the design of compounds capable of effectively targeting HER2, providing a clear biotechnology-related relevance that may lead to better strategies to fight breast cancer.

Co-PI:

Dr. Pradip Ramdas Chaudhari, Tata Memorial Centre (Hospital), Mumbai, Maharashtra-400012

Total Budget (INR):

47,32,640

Organizations involved