MLH1 Deficiency Induces Cetuximab Resistance in Colon Cancer via Her‐2/PI3K/AKT Signaling

The rapid onset of resistance to cetuximab (CTX) limits its clinical utility in colorectal cancer (CRC) patients. This study aims to understand a potential role of mismatch repair gene mutL homolog 1 (MLH1) in CTX response. Functional analysis of MLH1 in Her‐2/phosphoinositide 3‐kinases (PI3K)/PKB protein kinase (AKT)‐regulated CTX sensitivity is performed using human CRC specimens, CRC cell lines with different MLH1 expression levels, and a subcutaneous xenograft model. Overexpression, knockdown, small interfering RNA, and inhibitors are used to examine the role of MLH1 and HER‐2 downstream signaling and apoptotic targets in CTX sensitivity. Reduced MLH1 expression is correlated with unfavorable prognosis in cetuximab‐treated patients. MLH1 loss decreases CTX sensitivity through Her‐2/PI3K/AKT signaling and apoptosis resistance in culture and in xenografts, while MLH1 overexpression increases CTX sensitivity. Blocking Her‐2 signaling increases CTX sensitivity of microsatellite instability CRC in vitro and in vivo. MLH1 loss induces activation of Her‐2/PI3K/AKT signaling and leads to cetuximab resistance in colon cancer.