Abstract
N-myc downstream-regulated gene 1 (NDRG1) is a key regulator that interacts with many classic tumor signaling pathways, including some molecules downstream of the epidermal growth factor receptor (EGFR). However, whether NDRG1 is involved in the mechanism of resistance to cetuximab (CTX), the first monoclonal antibody targeting the EGFR has not been reported. Here, we found that NDRG1 enhanced the sensitivity of CTX in colorectal cancer (CRC) cell lines. Afterwards, we determined the underlying mechanism of this phenomenon. We demonstrated that NDRG1 inhibited the expression of EGFR; blocked EGFR phosphorylation and reduced the EGFR distribution in the cell membrane, cytoplasm and nucleus. And then, NDRG1 suppressed the EGFR downstream signaling: RAS/RAF/ERK and PI3k/AKT/mTOR pathways. Moreover, we discovered that NDRG1 attenuated the endocytosis and degradation of EGFR induced by caveolin-1 (Cav1). Additionally, our findings were further observed in an animal model and human tissues. Our results represent a potentially significant discovery that explains the mechanisms of NDRG1 in CTX resistance. NDRG1 could be a promising biomarker to predict optimum responses to CTX, and a key target to enhance CTX activity in the treatment of metastatic CRC (mCRC).
Highlights
Colorectal cancer (CRC) is one of the most common malignancies worldwide, with 1,880,725 new cases and 915,880 deaths in 2020, and the increasing incidence has not been reversed in recent years [1, 2]
N-myc downstream-regulated gene 1 (NDRG1) enhanced CTX sensitivity in CRC cell lines To identify the effect of NDRG1 on the response of CRC cells to CTX, we first used data from the public Gene Expression Omnibus (GEO) database
An apoptosis assay revealed that when both cell lines were challenged with CTX, NDRG1overexpressing cells showed a significantly increased apoptotic rate relative to that of the control group, and NDRG1-knockdown cells were more insensitive to CTX than control cells (Fig. 1E, F)
Summary
Colorectal cancer (CRC) is one of the most common malignancies worldwide, with 1,880,725 new cases and 915,880 deaths in 2020, and the increasing incidence has not been reversed in recent years [1, 2]. CTX, which is currently approved to treat mCRC patients with RAS wt tumors due to the insensitivity of RAS mutation tumors to CTX, has been included in the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines based on the results of many clinical trials [4,5,6]. Among these trials, the CALGB/SWOG 80405 trial reported that in KRAS wt tumors, the response rate to CTX treatment was 59.6%. It is necessary to further identify more precise biomarkers to evaluate CTX sensitivity to improve the therapeutic effect of individualized and comprehensive mCRC treatment
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