MLH1 Deficiency Induces Cetuximab Resistance in Colon Cancer via Her‐2/PI3K/AKT Signaling. Issue 13 (26th May 2020)

• Record Type: Journal Article
• Authors: Han, Ying; Peng, Yinghui; Fu, Yaojie; Cai, Changjing; Guo, Cao; Liu, Shanshan; Li, Yiyi; Chen, Yihong; Shen, Edward; Long, Kexin; Wang, Xinwen; Yu, Jian; Shen, Hong; Zeng, Shan
• Is Part Of: Advanced science. Volume 7:Issue 13(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-05-26
• Subjects: cetuximab -- colon cancer -- HER‐2 -- mutL homolog 1 -- phosphoinositide 3‐kinases pathway; Science -- Periodicals; 505
• DOI: 10.1002/advs.202000112
• Languages: English
• ISSNs: 2198-3844

Abstract

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. Abstract : Mismatch repair (MMR) genes deficiency can drive genomic instability and therapeutic resistance in colorectal cancer (CRC). Nevertheless, many of the mechanisms of MMR affecting drug resistance in CRC are still enigmatic. It is revealed that mutL homolog 1 deficiency decreases cetuximab sensitivity through Her‐2/phosphoinositide 3‐kinases/PKB protein kinase signaling, which provides a mechanism of overcoming cetuximab resistance potentially by HER‐2/epidermal growth factor receptor dual inhibition.