Tumor-specific degradation of EGFR and HER2 mediated by a CD36-directed proteolysis targeting chimera

Liu, Zheng, Li, Xiaolin, Gu, Yu, Zhong, Qiuling, Liu, Qian, Sloan, Alastair J. and Song, Bing ORCID: https://orcid.org/0000-0001-9356-2333 2026. Tumor-specific degradation of EGFR and HER2 mediated by a CD36-directed proteolysis targeting chimera. Journal of Pharmaceutical Analysis , 101749. 10.1016/j.jpha.2026.101749

PDF - Accepted Post-Print Version Available under License Creative Commons Attribution. Download (16MB)

Abstract

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are key oncogenic drivers in gastric and other solid tumors, yet the clinical benefit of conventional tyrosine kinase inhibitors such as lapatinib is limited by acquired resistance and incomplete pathway suppression. Proteolysis-targeting chimeras (PROTACs) provide an event-driven strategy for simultaneous target elimination, but their translation is often constrained by on-target, off-tumor toxicity in normal tissues expressing basal levels of EGFR/HER2. Here, we developed a series of lapatinib-derived PROTACs that recruit the von Hippel-Lindau (VHL) E3 ligase to induce dual degradation of EGFR and HER2. The lead compound, PROTAC-B7, showed superior antitumor activity to lapatinib, a selective EGFR degrader (PROTAC-A1), and a selective HER2 degrader (PROTAC-A2) in vitro and in vivo, but caused dose-limiting systemic toxicity. Mechanistically, we found that the fatty acid translocase CD36 mediates cellular uptake of fatty acid-conjugated PROTACs and is highly expressed in gastric cancer cells. Guided by this finding, we generated a second-generation molecule, PROTAC-B7.7, by conjugating PROTAC-B7 with a long-chain fatty acid. This modification enhanced CD36-dependent tumor cell uptake and intracellular accumulation, while reducing toxicity in normal cells with low CD36 expression. Consequently, PROTAC-B7.7 achieved more selective EGFR/HER2 degradation, stronger antitumor efficacy, and an improved therapeutic window in preclinical models. These findings establish CD36-mediated targeted delivery as a modular strategy to enhance the tumor selectivity and translational potential of PROTAC therapeutics.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Dentistry
Publisher:	Elsevier
ISSN:	2095-1779
Date of First Compliant Deposit:	18 August 2026
Date of Acceptance:	11 August 2026
Last Modified:	18 Aug 2026 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/189061

Actions (repository staff only)

Edit Item