Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models
Nakazawa, Y. et al. (2024) Delivery of a BET protein degrader via a CEACAM6-targeted antibody–drug conjugate inhibits tumour growth in pancreatic cancer models. Nature. Communications. 15:2192. DOI:10.1038/s41467-024-46167-1.
This study focuses on the development of a novel therapeutic approach for treating pancreatic ductal adenocarcinoma (PDAC), a cancer with notoriously poor prognosis. Researchers developed an antibody-drug conjugate (ADC) that targets the CEACAM6 protein, overexpressed in PDAC cells. The payload for this ADC is a newly identified BET protein degrader (EBET), designed to degrade bromodomain and extra-terminal (BET) proteins, which are crucial for cancer cell survival and proliferation. The study demonstrated that the CEACAM6-targeted ADC (84-EBET) effectively killed PDAC cells in vitro, especially in organoid cultures that closely mimic the in vivo tumor environment. Additionally, 84-EBET showed a significant tumor regression effect in various PDAC-patient-derived xenograft (PDX) models without causing substantial toxicity. Importantly, the ADC exhibited a bystander effect, killing not only CEACAM6-positive cancer cells but also affecting the tumor microenvironment, including cancer-associated fibroblasts (CAFs), which play a role in the immunosuppressive microenvironment of PDAC. Combination therapies with standard chemotherapy or PD-1 antibody further enhanced the therapeutic efficacy of 84-EBET, suggesting potential for this ADC in improving outcomes for PDAC patients.
Keywords: BET protein degrader, CEACAM6, antibody-drug conjugate, pancreatic ductal adenocarcinoma, PDAC, tumor microenvironment, bystander effect, organoids, xenografts
