Journal Article Review Epublish
PubMed: 40656600 DOI: 10.1177/17588359251353623
Understanding and overcoming CDK4/6 inhibitor resistance in HR+/HER2- metastatic breast cancer: clinical and molecular perspectives.
Ther Adv Med Oncol 17:17588359251353623
Authors: Jessé Lopes da Silva, Leandro Jonata de Carvalho Oliveira, Cristiano Augusto Andrade de Resende, Tomas Reinert, Lucas Zanetti de Albuquerque, Luís Felipe Leite da Silva, Max Senna Mano
Affiliations
- Division of Clinical Research and Technological Development, Brazilian National Cancer Institute, 37 Andre Cavalcanti Street, 5th Floor, Annex Building, Rio de Janeiro 20231050, Brazil.
- Oncoclínicas&Co, São Paulo, Brazil.
- Grupo Brasileiro de Estudos em Câncer de Mama, Porto Alegre, Brazil.
- Hospital Nora Teixeira, Santa Casa de Porto Alegre, Porto Alegre, Brazil.
- Division of Clinical Research and Technological Development, Brazilian National Cancer Institute, Rio de Janeiro, Brazil.
- Department of Medical Sciences, Federal Fluminense University, Rio de Janeiro, Brazil.
- Hospital Israelita Albert Einstein, São Paulo, Brasil.
Abstract
This narrative review explores the mechanisms underlying resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor (HR)-positive metastatic breast cancer (MBC), a critical challenge in contemporary oncology. Despite the proven efficacy of CDK4/6i in improving clinical outcomes, both intrinsic and acquired resistance remain substantial challenges. We discuss clinical data that underscore pivotal molecular alterations associated with resistance, including mutations in the Retinoblastoma gene (RB1), germline variants, aberrations in the PIK3CA gene that activate the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin signaling cascade, and modifications in fibroblast growth factor receptor signaling. Additional resistance mechanisms-such as the loss of the FAT1 tumor suppressor gene and the dysregulation of cell cycle regulators like cyclin E and CDK2-are also explored. The role of circulating tumor DNA analysis in tracking genomic changes during therapy is also considered. Furthermore, the review assesses emerging therapeutic strategies, particularly combination therapies that target alternative pathways to counteract resistance mechanisms. By synthesizing current evidence and providing actionable insights, this review aims to enhance our understanding of endocrine resistance mechanisms among clinical oncologists and gives them some future perspectives to expand strategies to overcome this challenge.
MeSH
Genes, Protein Kinases, Breast Neoplasms, Neoplasms, Cyclins, Breast, Therapeutics