Targeting FAK Improves the Tumor Uptake of ADCs

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.  WuXi AppTec contributed to a research article which demonstrated that excessive cancer-associated fibroblasts (CAFs) can form a fibrotic barrier within a tumor microenvironment, impeding the tissue uptake of ADCs and dampening anti-tumor efficacy.

Mechanistically, cancer cells transform normal fibroblasts into focal adhesion kinase (FAK)-activated CAFs.  In this study, the authors show that targeting FAK with a small molecule inhibitor (IN10018) effectively diminishes the CAF-associated tumor barrier, enhancing the tumor uptake of various ADCs irrespective of their specific targets.