Profiling EGFR, c-MET, and B7H3 co-expression to guide next-generation dual-drug conjugate strategies in colorectal cancer

Abstract

Epidermal growth factor receptor (EGFR), cellular mesenchymal-epithelial transition factor (c-MET), and B7 homolog 3 (B7H3) are important targets for antibody-based drug development in colorectal cancer (CRC). To overcome the limitations of single-target antibody therapies – such as limited efficacy, widespread resistance, narrow patient populations, and treatment-related toxicities – various bispecific antibodies or antibody–drug conjugate (ADCs) targeting two targets are being extensively validated in clinical settings. A deeper understanding of their expression profiles and co-expression patterns of actionable therapeutic targets may guide more effective treatment strategies. We evaluated the immunohistochemical expression of B7H3, c-MET, and EGFR in a cohort of 193 CRC patients. Among which, B7H3 exhibited the highest positivity rate (80.83%) in CRC tissues, followed by c-MET (77.20%) and EGFR (47.15%). The positive rates of B7H3 showed no significant differences across patient gender, age, TNM stage, differentiation grade, or tumor site. In contrast, the c-MET positivity rate was elevated in patients with stage I–II disease, and the expression of EGFR was significantly higher in female patients than in male patients. Concurrent assessment of the three targets in metastatic lesions revealed that B7H3 expression levels were comparable between primary and metastatic tumors, whereas c-MET expression was significantly higher in primary lesions. Co-expression analysis indicated that the group with the highest patient coverage was the B7H3/c-MET dual-positive group, followed by the B7H3/EGFR, and c-MET/EGFR combinations, and the proportion of patients with at least one positive target exceeded 80%. Finally, mRNA profile from TIMER database reveals that CD276 and MET expression in CRC tumor tissues were higher than those in the majority of normal tissues. Therefore, utilizing B7H3/c-MET combination therapies that integrate intracellular signaling inhibition with immune checkpoint modulation could potentially extend therapeutic benefits to a wider range of CRC patients.