Mechanisms of resistance to anti-HER2 drugs used in breast cancer

• Autor(a) principal: Matias, Adriana Patrícia Freitas
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10773/39308
• topic: Breast cancer; Antibody-drug conjugates; T-DM1; T-DXd; Resistance mechanisms; Lysosomes

Breast cancer is the most diagnosed cancer among women worldwide and the development of various molecular technologies has allowed the creation of a classification system into different molecular subtypes. The HER2-overexpressing subtype occurs in 15-20% of all breast cancers, being associated with the overexpression of HER2. HER2 is a member of the human epidermal growth factor receptor (HER) family, which has been involved in cancer genesis and progression. HER2 became an important therapeutic target for the treatment of HER2-positive breast cancer. Recently, a new group of anti-HER2 therapies emerged, the Antibody-Drug Conjugates, or ADCs. These molecules, comprised of an antibody attached to a cytotoxic payload via a linker, are specifically designed to selectively direct a chemotherapeutic agent and its cytotoxic effects to cancer cells that express a specific target on the cell surface. Several efforts have been made to identify potential mechanisms of resistance to ADCs, especially to T-DM1. However, little is known about the mechanisms of resistance to the recently approved T-DXd. For that reason, we aimed to identify those mechanisms using T-DXd-resistant cell models, as well as to study the effect of this drug in T-DM1-resistant cells. In this study, we first analyzed the effect of T-DXd in T-DM1 and T-DXd-resistant cells (BT-TDM1R#1 and BT-DxRpool, respectively) and detected that T-DM1-resistant cells were also partially resistant to T-DXd. Because of this, we proceeded with the use of these two models of resistance for our studies and identified that both BT-TDM1R#1 and BT-DxRpool cells accumulated T-DM1 and T-DXd in intracellular vesicles, coinciding with lysosomes. However, this accumulation was more evident in BT-TDM1R#1 cells, pointing to different mechanisms of resistance to both drugs. To better study the mechanisms of resistance to T-DXd, we generated several resistant clones to this drug and identified that different clones may have different mechanisms of resistance to T-DXd, as some of them accumulated the drug similar to BT-TDM1R#1 cells, and others did not. Also, some of these clones showed partial resistance to T-DM1. Our data indicated that different resistant cells could present different resistance mechanisms to T-DXd. In addition, since both T-DM1 and T-DXd share the initial steps of internalization, they could also share some mechanisms of resistance.