Cetuximab enhances the efficiency of irinotecan through simultaneously inhibiting the MAPK signaling and ABCG2 in colorectal cancer cells

Ge, Xiaojun; Jiang, Junyao; Wang, Mei; Li, Mei‐Yong; Zheng, Limei; Feng, Zhongxin; Liu, Lan

doi:10.1016/j.prp.2019.152798

Cited by 7 publications

(5 citation statements)

References 20 publications

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“…Similarly, an inhibitor of TWIST1 signalling had anti‐tumour activity in patient‐derived xenograft models of non‐small lung cancer [ 28 ]. In terms of clinically approved drugs which target EMT‐related proteins, anti‐EGFR therapeutic cetuximab is currently utilised for metastatic CRC [ 29 ]. Future work should include establishing the potential for cetuximab in TMS3 tumours specifically across stage I–III disease.…”

Section: Discussionmentioning

confidence: 99%

Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer

Hatthakarnkul,

Pennel,

Alexander

et al. 2024

The Journal of Pathology CR

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Colorectal cancer (CRC) is a heterogenous malignancy and research is focused on identifying novel ways to subtype patients. In this study, a novel classification system, tumour microenvironment score (TMS), was devised based on Klintrup–Mäkinen grade (KMG), tumour stroma percentage (TSP), and tumour budding. TMS was performed using a haematoxylin and eosin (H&E)‐stained section from retrospective CRC discovery and validation cohorts (n = 1,030, n = 787). TMS0 patients had high KMG, TMS1 were low for KMG, TSP, and budding, TMS2 were high for budding, or TSP and TMS3 were high for TSP and budding. Scores were assessed for association with survival and clinicopathological characteristics. Mutational landscaping and Templated Oligo‐Sequencing (TempO‐Seq) profiling were performed to establish differences in the underlying biology of TMS. TMS was independently prognostic in both cohorts (p < 0.001, p < 0.001), with TMS3 predictive of the shortest survival times. TMS3 was associated with adverse clinical features including sidedness, local and distant recurrence, higher T stage, higher N stage, and presence of margin involvement. Gene set enrichment analysis of TempO‐Seq data showed higher expression of genes associated with hallmarks of cancer pathways including epithelial to mesenchymal transition (p < 0.001), IL2 STAT5 signalling (p = 0.007), and angiogenesis (p = 0.017) in TMS3. Additionally, enrichment of immunosuppressive immune signatures was associated with TMS3 classification. In conclusion, TMS represents a novel and clinically relevant method for subtyping CRC patients from a single H&E‐stained tumour section.

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Section: Discussionmentioning

confidence: 99%

Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer

Hatthakarnkul,

Pennel,

Alexander

et al. 2024

The Journal of Pathology CR

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“…In other types of cancer, HA-CD44 binding also plays a role in triggering signals from later receptors in the tyrosine kinase family (such as EGFR), leading to PI3K/Akt or MAPK pathway activation [ 66 ]. Monoclonal antibodies against EGFR are commonly used in the treatment of metastatic colorectal cancer, and some of these agents synergistically inhibit both EGFR phosphorylation and ABCG2 drug efflux activity [ 67 , 68 , 69 ]. EGFR was also found to exert a post-transcriptional effect on ABCG2 expression via the PI3K/AKT and RAS/RAF/MEK/ERK signalling pathways [ 63 , 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer—In Silico and Wet Analysis

Sałagacka-Kubiak,

Zawada,

Saed

et al. 2023

IJMS

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ABCG2 (ATP-binding cassette superfamily G member 2) is a cell membrane pump encoded by the ABCG2 gene. ABCG2 can protect cells against compounds initiating and/or intensifying neoplasia and is considered a marker of stem cells responsible for cancer growth, drug resistance and recurrence. Expression of the ABCG2 gene or its protein has been shown to be a negative prognostic factor in various malignancies. However, its prognostic significance in colorectal cancer remains unclear. Using publicly available data, ABCG2 was shown to be underexpressed in colon and rectum adenocarcinomas, with lower expression compared to both the adjacent nonmalignant lung tissues and non-tumour lung tissues of healthy individuals. This downregulation could result from the methylation level of some sites of the ABCG2 gene. This was connected with microsatellite instability, weight and age among patients with colon adenocarcinoma, and with tumour localization, population type and age of patients for rectum adenocarcinoma. No association was found between ABCG2 expression level and survival of colorectal cancer patients. In wet analysis of colorectal cancer samples, neither ABCG2 gene expression, analysed by RT-PCR, nor ABCG2 protein level, assessed by immunohistochemistry, was associated with any clinicopathological factors or overall survival. An ABCG2-centered protein–protein interaction network build by STRING showed proteins were found to be involved in leukotriene, organic anion and xenobiotic transport, endodermal cell fate specification, and histone methylation and ubiquitination. Hence, ABCG2 underexpression could be an indicator of the activity of certain signalling pathways or protein interactors essential for colorectal carcinogenesis.

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“…Although the classic tumorigenesis pathway focusing on APC / KRAS / TP53 mutations has been established well in CRC 39 , 40 , the diverse biochemical properties of KRAS mutational isoforms to hydrolyze GTP and activate downstream signaling pathways still challenge scientists and physicians dramatically 41 , 42 . Moreover, metastatic CRC carrying KRAS mutations shows remarkable resistance to cetuximab due to the integrated activation of the RAS-RAF-MEK-ERK pathway 43 , 44 . Thus, it is interesting to explore the risk factors associated with KRAS mutations to elucidate pathogenesis and evaluate prognosis in CRC.…”

Section: Discussionmentioning

confidence: 99%

The Contributions of Trace Elements on Molecular Subtype-Specific Colorectal Cancer

Bai,

Xiao,

Huang

et al. 2023

J. Cancer

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Purpose: Although growing studies have reported the disturbances of trace elements (TEs) homeostasis was closely associated with the occurrence of colorectal cancer (CRC), the clinical value of TEs in CRC with different molecular subtypes was largely unknown. This study aimed to explore the correlation between KRAS mutations/MSI status and serum TEs levels in patients with CRC. Methods: The serum concentrations of 18 TEs were detected by inductively coupled plasma emission spectrometry (ICP-MS). MSI status (two mononucleotides: BAT25, BAT26, three dinucleotides: D2S123, D5S346, and D17S250), KRAS (G516T, G517A, G518C, G520T, G521A, G522C, and G532A) mutations were detected by the multiplex fluorescent PCR and the real-time fluorescent quantitative PCR, respectively. The correlations among KRAS mutations/MSI status, demographic and clinical characteristics, and TEs were analyzed by Spearman correlation analysis. Results: The propensity score matching (PSM) analysis was adopted to minimize differences between groups. Before PSM, 204 CRC patients were recruited in this study, including 123 KRAS -negative patients and 81 KRAS -positive patients according to the test results of KRAS mutations, and 165 MSS patients and 39 MSI patients based on MSI detection. After PSM, the serum concentration of Mn was significantly lower in CRC patients with KRAS mutations than those without KRAS mutations, and a significant negative correlation was observed between Mn and Pb in the KRAS -positive cases. CRC patients carrying MSI had a significantly lower level of Rb compared to MSS patients. Importantly, Rb was significantly positively correlated with Fe, Mn, Se, and Zn in patients with MSI. Collectively, all our data indicated that the occurrence of different molecular events might be accompanied by different alterations in types and levels of serum TEs. Conclusions: CRC patients with different molecular subtypes presented different alterations in types and levels of serum TEs. Mn was significantly negatively correlated with the KRAS mutations, and Rb was noticeably negatively correlated with the MSI status, indicating certain TEs might contribute to the pathogenesis of molecular subtype-specific colorectal cancer.

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Cetuximab enhances the efficiency of irinotecan through simultaneously inhibiting the MAPK signaling and ABCG2 in colorectal cancer cells

Cited by 7 publications

References 20 publications

Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer

Histopathological tumour microenvironment score independently predicts outcome in primary operable colorectal cancer

ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer—In Silico and Wet Analysis

The Contributions of Trace Elements on Molecular Subtype-Specific Colorectal Cancer

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