Overcoming EGFR Resistance in Metastatic Colorectal Cancer Using Vitamin C: A Review

Abstract

Targeted monoclonal antibody therapy against Epidermal Growth Factor Receptor (EGFR) is a leading treatment modality against metastatic colorectal cancer (mCRC). However, with the emergence of KRAS and BRAF mutations, resistance was inevitable. Cells harboring these mutations overexpress Glucose Transporter 1 (GLUT1) and sodium-dependent vitamin C transporter 2 (SVCT2), which enables intracellular vitamin C transport, leading to reactive oxygen species generation and finally cell death. Therefore, high dose vitamin C is proposed to overcome this resistance. A comprehensive search strategy was adopted using Pubmed and MEDLINE databases (up to 11 August 2022). There are not enough randomized clinical trials to support its use in the clinical management of mCRC, except for a subgroup analysis from a phase III study. High dose vitamin C shows a promising role in overcoming EGFR resistance in mCRC with wild KRAS mutation with resistance to anti-epidermal growth factor inhibitors and in patients with KRAS and BRAF mutations.

Influence of Clinical Factors on miR-3613-3p Expression in Colorectal Cancer

“…EGFR-targeted therapy was confirmed to increase overall survival by 10–20% in colorectal cancer. With the emergence of KRAS and BRAF mutations, resistance to EGFR-targeted therapy has developed, driven by mechanisms affecting both cellular pathways and the tumor microenvironment [ 44 ]. The kinase-activating mutations that result in enhanced EGFR tyrosine kinase activity might occur as a result of, or in addition to, anti-EGFR therapy [ 42 ].…”

GLUT1 promotes cell proliferation via binds and stabilizes phosphorylated EGFR in lung adenocarcinoma

“…As the primary glucose transporter [14], GLUT1 supports glycolysis and mediates a complex series of tumor metabolism reprogramming events [15,16]. Several studies have suggested that GLUT1 may contribute to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance by mediating glucose metabolism [17][18][19]. Clinical studies have reported a correlation between EGFR expression [20] and mutation status [21] with GLUT1 expression.…”

From Antioxidant to Anticancer is Vitamin C Effective in Colorectal Cancer?

“…When cultured with mM doses of ascorbate, cancer cells with mutations in KRAS, and BRAF were demonstrated to uptake DHA via GLUT1, which was linked to a reduction in cell survival [ 8 ]. Furthermore, by modifying several signaling pathways, lowering important checkpoints, obstructing anaerobic glycolysis and angiogenesis, and upsetting their Warburg metabolism, while also preserving the health of colon cells [ 9 ]. Concurrent vitamin C delivery also has been shown to significantly alleviate chemotherapy-related side effects like constipation, sleeplessness, and exhaustion [ 3 ].…”