afatinib + selumetinib

Afatinib + selumetinib is a combination therapy that targets both the EGFR and MEK pathways. Afatinib is a pan-HER inhibitor that covalently binds to and irreversibly blocks signaling from all homo and heterodimers formed by the ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. Selumetinib is a selective MEK1/2 inhibitor that blocks the RAS-RAF-MEK-ERK signaling cascade. The combination was developed to overcome resistance mechanisms in KRAS-mutated tumors, where MEK inhibitors alone have limited efficacy due to feedback activation of upstream epidermal growth factor receptors. This upstream activation not only reactivates MAPK but also the phosphoinositide 3-kinase (PI3K)-AKT pathway.