Targeting FAK improves the tumor uptake of antibody-drug conjugates to strengthen the anti-cancer responses.

ABSTRACT: Antibody-drug conjugates (ADCs), exemplified by HER2-targeted Enhertu and TROP2-targeted Trodelvy, have demonstrated significant therapeutic potential in cancers. However, a subset of patients remains refractory to ADC treatment, suggesting that the efficacy requires further optimization. Here, we demonstrate that excessive cancer-associated fibroblasts (CAFs) can form a fibrotic barrier, impeding the tissue uptake of ADCs to dampen the anti-tumor efficacy. Mechanistically, cancer cells transform normal fibroblasts into FAK-activated CAFs. The proliferation of these CAFs reduces the tumor uptake of macromolecular drugs, conferring resistance to ADCs. Targeting FAK with a small molecule inhibitor IN10018 effectively diminishes the CAF-associated tumor barrier, enhancing the tumor uptake of

SUBMITTER: Zhang B 

PROVIDER: S-EPMC11879607 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature