Investigating the role of MMP14, B7-H3, PTK7, and LRRC15 in head and neck cancers: Implications for antibody-drug conjugates

Abstract

Despite significant advancements in cancer treatment, Head and Neck cancers (HNSCs) remain challenging to manage, necessitating the exploration of novel therapeutic strategies. To this extent, clinical trials are investigating the potential of antibody-drug conjugates (ADCs) targeting Matrix-Metalloproteinase14 (MMP14), B7-Homolog3 (B7-H3), Protein Tyrosine Kinase7 (PTK7) and Leucine-Rich Repeat Containing15 (LRRC15), as candidate target antigens for HNSCs. MMP14 is a membrane-bound matrix metalloproteinase involved in extracellular matrix (ECM) remodeling. B7-H3, an immune checkpoint protein involved in immune modulation and escape. PTK7 is a protein tyrosine kinase receptor involved in Wnt/β-Catenin signaling and cancer stem cell (CSC) regulation. LRRC15 is a cancer-associated fibroblasts (CAFs) marker implicated in tumor aggressiveness. These genes are commonly overexpressed in HNSC tumor microenvironment (TME) and negatively correlated with HNSC patient survival. Therefore, we suggest that targeting these molecules with ADCs holds significant potential to disrupt critical pathways associated with ECM remodeling, immune evasion, CSC regulation, and CAF-mediated tumor aggressiveness, ultimately improving therapeutic outcomes in HNSCs. Utilizing bioinformatics analysis, we identify that TGF-β3 activation of LRRC15+ CAFs and membrane metalloproteinase MMP14 may interact with B7-H3 and PTK7 through the intermediate substrates Periostin (POSTN) and matrix metalloproteinase 2 (MMP2) using the STRING Database. Next, we showed that MMP14, B7-H3 PTK7 and LRRC15 are overexpressed in HNSC and differentially expressed compared to normal cells. We then demonstrated the strong correlation between MMP14, B7-H3, and PTK7 and between MMP14, MMP2 and LRRC15 expressions in HNSC patient datasets. We then modeled the Protein-Protein Interactions between MMP14-B7H3, MMP14-PTK7, B7H3-PTK7, MMP14-LRRC15. We subsequently showed the potential of B7-H3 to function as a prognostic marker in HNSC due to its increased expression being negatively correlated with patient survival and propose a mechanism in which B7-H3 interaction with MMP14, PTK7, LRRC15 through POSTN, MMP2, and TGF-β3 increases the ability for CSCs to evade immune regulation. Finally, we analyzed ADCs targeting B7-H3, MMP14, PTK7 and LRRC15 that are undergoing clinical trials and suggest how targeting these antigens will increase the therapeutic efficacy of these ADCs in HNSCs.