Abstract
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.
Highlights
Introduction ing to constitutive activeepidermal growth factor receptor (EGFR) signaling, which negatively affect response to EGFR monoclonalColorectal carcinoma (CRC) is one of the most common can- antibodies.[9]
We first examined in CTX-treated training cohort (N = 102, with 40 months follow up) of mutL homolog 1 (MLH1) protein expression by immunohistochemistry (IHC) MLH1 protein was mainly located in the nucleus of cancer cells (Figure 1A) and its reduction was found to be associated with poor prognosis
Genetic activation of KRAS, NRAS, HER2, and MET or upregulation of EGFR, HER-2, and HER-3 IGF1R can lead to acquired resistance to cetuximab.[25,26,27]
Summary
Introduction ing to constitutive activeEGFR signaling, which negatively affect response to EGFR monoclonalColorectal carcinoma (CRC) is one of the most common can- antibodies.[9]. EGFR signaling, which negatively affect response to EGFR monoclonal. Colorectal carcinoma (CRC) is one of the most common can- antibodies.[9] Cetuximab is ineffective in CRC patients harcers worldwide. Colon cancer patients diagnosed with distant boring KRAS or BRAF mutations. Zeng Key Laboratory for Molecular Radiation Oncology of Hunan Province Xiangya Hospital Central South University Changsha, Hunan 410008, China
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