bims-instec 2022-04-03 papers

Signal Transduct Target Ther. 2022 Mar 30. 7(1): 87

Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer.

Yimin Li, Yaqi Gan, Jiaxin Liu, Juanni Li, Zhengwei Zhou, Ruotong Tian, Ruizheng Sun, Jiaqi Liu, Qing Xiao, Yuanyuan Li, Pengyan Lu, Yulong Peng, Yuqian Peng, Guang Shu, Gang Yin.

Oxaliplatin is widely used in the frontline treatment of colorectal cancer (CRC), but an estimated 50% of patients will eventually stop responding to treatment due to acquired resistance. This study revealed that diminished MEIS1 expression was detected in CRC and harmed the survival of CRC patients. MEIS1 impaired CRC cell viabilities and tumor growth in mice and enhanced CRC cell sensitivity to oxaliplatin by preventing DNA damage repair. Mechanistically, oxaliplatin resistance following MEIS1 suppression was critically dependent on enhanced FEN1 expression. Subsequently, we confirmed that EZH2-DNMT3a was assisted by lncRNA ELFN1-AS1 in locating the promoter of MEIS1 to suppress MEIS1 transcription epigenetically. Based on the above, therapeutics targeting the role of MEIS1 in oxaliplatin resistance were developed and our results suggested that the combination of oxaliplatin with either ELFN1-AS1 ASO or EZH2 inhibitor GSK126 could largely suppress tumor growth and reverse oxaliplatin resistance. This study highlights the potential of therapeutics targeting ELFN1-AS1 and EZH2 in cell survival and oxaliplatin resistance, based on their controlling of MEIS1 expression, which deserve further verification as a prospective therapeutic strategy.

DOI: https://doi.org/10.1038/s41392-022-00902-6

Front Pharmacol. 2022 ;13 851401

HIF1α/VEGF Feedback Loop Contributes to 5-Fluorouracil Resistance.

Bin Shi, Fang-Fang Xu, Cai-Ping Xiang, Chuan-Yan Li, Ping Fan, Hao Wang.

5-Fluorouracil (5-Fu) is one of the basic drugs in colorectal cancer (CRC) chemotherapy, and its efficacy is mainly limited by the acquisition of drug resistance. However, the underlying mechanisms remain unclear. In this study, hypoxia inducible factor 1α (HIF1α) was screened for high expression in 5-Fu resistant HCT115 cells, which displayed epithelial-mesenchymal transition (EMT) phenotype. Suppression of HIF1α reversed EMT phenotype, reduced glucose transporter 1 (Glut1) expression, a key molecule mediated drug resistance. Moreover, we unveiled that vascular endothelial growth factor (VEGF) was regulated by HIF1α and mediated HIF1α-maintained malignant phenotype of 5-Fu resistant cells. Further studies verified that AKT/GSK3β signaling was activated in resistant cells and controlled HIF1α expression. Interestingly, we demonstrated that VEGF could feedback up-regulate HIF1α via AKT/GSK3β signaling. Clinically, HIF1α and VEGF were high expressed and associated with survival and prognosis in CRC patients. In conclusion, our findings proposed that HIF1α/VEGF feedback loop contributed to 5-Fu resistance, which might be potential therapeutic targets.

Keywords: Akt/GSK3β; EMT; GLUT1; HIF1α; VEGF; drug resistance

DOI: https://doi.org/10.3389/fphar.2022.851401

Crit Rev Oncol Hematol. 2022 Mar 25. pii: S1040-8428(22)00070-1. [Epub ahead of print]173 103646

Systematic review of randomised clinical trials and observational studies for patients with RAS wild-type or BRAFV600E-mutant metastatic and/or unresectable colorectal cancer.

Pilar García-Alfonso, Astrid Lièvre, Fotios Loupakis, Abir Tadmouri, Sadya Khan, Leticia Barcena, Sebastian Stintzing.

Approximately 8-10% of metastatic colorectal cancer (mCRC) tumours harbour BRAFV600E mutations. Eleven randomised controlled trials (RCTs) and 24 non-RCTs were identified. Seven studies evaluated BRAF inhibitors. Single-agent BRAF inhibitors had minimal efficacy, whereas BRAF inhibitor plus anti-EGFR therapy improved outcomes. In BEACON CRC, overall survival (OS) was significantly longer for patients receiving encorafenib plus cetuximab ± binimetinib when compared with irinotecan/FOLFIRI plus cetuximab as second- and third-line therapy. Seven prospective non-RCTs reported worse OS and progression-free survival (PFS) for patients with BRAFV600E-mutant vs BRAF wild-type mCRC. Eight RCTs reported that PFS and OS were generally shorter for patients with BRAFV600E-mutant mCRC vs those with KRAS or RAS wild-type mCRC. Patients with BRAFV600E-mutant mCRC have worse outcomes with conventional therapy vs patients with BRAF wild-type tumours. BRAF inhibitors in conjunction with anti-EGFR therapy improves outcomes for patients with BRAFV600E-mutant mCRC vs conventional therapy or a BRAF inhibitor alone.

Keywords: BRAF kinase inhibitor; BRAFV600E; Efficacy; Metastatic colorectal cancer

DOI: https://doi.org/10.1016/j.critrevonc.2022.103646