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FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc.

ABSTRACT: Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was highly expressed in cetuximab resistant CRC tissues compared with cetuximab sensitive tissues. We therefore further analyzed its function in induced cetuximab resistant RAS-WT CRC cells (Caco2-CR) and intrinsic resistant cells with BRAF mutation (HT29). We found that FoxO3a was significantly up-regulated in Caco2-CR as well as in cetuximab treated HT29 cells. Knockdown of FoxO3a could sensitize these cells to cetuximab treatment with reduced cell proliferation and migration ability. Further, biochemical experiments demonstrated that FoxO3a directly bind to c-Myc promoter and activated the transcription of the c-Myc gene, thus participated in regulating of c-Myc downstream genes, including ACO2, LARS2, MRPL12 and PKM2 in these resistant cells. Moreover, knockdown of c-Myc elevated cell apoptosis to cetuximab treatment and suppressed cell proliferation and migration ability consistently. Altogether, our study indicates that FoxO3a might be a key regulator in cetuximab resistance through up-regulating c-Myc in colorectal cancer targeted therapy.

SUBMITTER: Yu Y

PROVIDER: S-EPMC5348362 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc.

Yu Yiyi Y Guo Mengzhou M Wei Ye Y Yu Shan S Li Hong H Wang Yan Y Xu Xiaojing X Cui Yuehong Y Tian Jiawen J Liang Li L Peng Ke K Liu Tianshu T

Oncotarget 20161201 49

Resistance to epidermal growth factor receptor (EGFR) targeted monoclonal antibody therapy represents a clinical challenge in patients suffered from RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, the molecular mechanisms and key factors conferring this resistance are largely unknown. Forkhead transcription factors of the O class 3a (FoxO3a), an important regulator of cell survival, has been reported with dual functions in tumor recently. In this study, we found that FoxO3a was ...[more]

PMID: 27825133

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Project description:BackgroundThis study sought to explore the biological significance of genetic variation in RAS wild-type metastatic colorectal cancer (mCRC) in the real world, the difference in the efficacy of cetuximab in the treatment of mCRC with different genetic variants and identify clinical features and new predictors of efficacy.MethodsA retrospective analysis of the data of 60 patients with stage IV mCRC who received cetuximab at The First and Second Affiliated Hospital of Soochow University from 2016 to 2020 was conducted. The patients were divided into the following 3 groups according to the genetic test results: (I) group A (the all-RAS wild-type group); (II) group B (the all-RAS wild-type group with the tumor suppressor gene mutation); and (III) group C (the all-RAS wild-type group with the oncogenic driver gene mutation). A subgroup analysis was conducted to examine left CRC and local intervention, and the progression-free survival (PFS) and overall survival (OS) of the patients were observed.ResultsThe all-RAS wild-type mCRC patients were divided into group A (n=10), group B (including the TP53, APC, PTEN, BRCA2, and SMAD4 variants) (n=42), and group C (including the ERBB2, BRAF, PIK3CA, and RET variants) (n=8). The median PFS of groups A, B, and C were 15.0, 12.0, and 3.0 months, respectively (P=0.007). Fitting sex as a stratified variable to the Cox survival analysis model showed that only the PFS of groups B and C differed significantly (P=0.011). In the left-sided mCRC patients, the median PFS of groups A, B, C were 3.0, 13.0, and 3.0 months, respectively (P=0.009). Among the patients in group B, the median PFS of the metastatic local intervention subgroup was 14.0 months, and the non-local intervention subgroup was 12.0 months (P=0.55). Only the type of combined gene mutation was an independent factor affecting PFS.ConclusionsThe PFS and OS of mCRC patients with all-RAS wild-type and no combined mutations treated with cetuximab were not better than those of patients with combined mutations. Compared to mCRC patients with all-RAS wild-type and oncogenic driver gene mutations, cetuximab significantly prolonged the PFS of all-RAS wild-type patients with the tumor suppressor gene mutations.

Dataset Information

FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc.

Publications

FoxO3a confers cetuximab resistance in RAS wild-type metastatic colorectal cancer through c-Myc.

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