Genomic Mapping of Epidermal Growth Factor Receptor and Mesenchymal–Epithelial Transition-Up-Regulated Tumors Identifies Novel Therapeutic Opportunities

SIMPLE SUMMARY: The identification of proteins in the cellular membrane of the tumoral cell is a key to the design and guidance of therapeutic agents. Recently, a bi-specific antibody termed amivantamab, targeting epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET), which are oncogenic membrane proteins, received regulatory approval for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). In this study, the authors explored tumor types with high levels of expression of EGFR and MET and focused on prostate adenocarcinoma and pancreatic adenocarcinoma, where anti-PD(L)1 agents alone have not shown relevant signs of activity. In addition, the authors confirmed that high expression of either receptor is associated with poor response to anti-PD(L)1 therapy, independently of the expression of PD-L1, suggesting that blocking these receptors with bi-specific EGFR/MET antibodies could augment the efficacy of anti-PD(L)1 inhibitors. ABSTRACT: Background: The identification of proteins in the cellular membrane of the tumoral cell is a key to the design of therapeutic agents. Recently, the bi-specific antibody amivantamab, targeting the oncogenic membrane proteins EGFR and MET, received regulatory approval for the treatment of adult patients with locally advanced or metastatic NSCLC. Methods: The authors interrogated several publicly available genomic datasets to evaluate the expression of both receptors and PD-L1 in most of the solid and hematologic malignancies and focused on prostate adenocarcinoma (PRAD) and pancreatic adenocarcinoma (PAAD). Results: In PAAD, EGFR highly correlated with PD-L1 and MET, and MET showed a moderate correlation with PD-L1, while in PRAD, EGFR, MET and PD-L1 showed a strong correlation. In addition, in tumors treated with immune checkpoint inhibitors, including anti-PD(L)1 and anti-CTLA4, a high expression of EGFR and MET predicted detrimental survival. When exploring the relationship of immune populations with these receptors, the authors observed that in PAAD and PRAD, EGFR moderately correlated with CD8+ T cells. Furthermore, EGFR and MET correlated with neutrophils in PRAD. Conclusions: The authors identified tumor types where EGFR and MET were highly expressed and correlated with a high expression of PD-L1, opening the door for the future combination of bi-specific EGFR/MET antibodies with anti-PD(L)1 inhibitors.