TY - JOUR
T1 - The Second Generation Antibody-Drug Conjugate SYD985 Overcomes Resistances to T-DM1
AU - Nadal-Serrano, Mercedes
AU - Morancho, Beatriz
AU - Escrivá-de-Romaní, Santiago
AU - Bernadó Morales, Cristina
AU - Luque, Antonio
AU - Escorihuela, Marta
AU - Espinosa-Bravo, Martín
AU - Peg, Vicente
AU - Dijcks, Fred A.
AU - Dokter, Wim H. A.
AU - Cortés, Javier
AU - Saura Manich, Cristina
AU - Arribas, Joaquín V
PY - 2020
Y1 - 2020
N2 - Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms-HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps-account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.
AB - Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms-HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps-account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.
KW - Breast cancer
KW - HER2
KW - Antibody-drug conjugate
KW - SYD985
KW - T-DM1
KW - Patient-derived xenograft
U2 - 10.3390/cancers12030670
DO - 10.3390/cancers12030670
M3 - Article
C2 - 32183023
SN - 2072-6694
VL - 12
JO - Cancers
JF - Cancers
ER -
