Vitamin C Restricts the Emergence of Acquired Resistance to EGFR-Targeted Therapies in Colorectal Cancer

Abstract

The long-term efficacy of the Epidermal Growth Factor Receptor (EGFR)-targeted antibody cetuximab in advanced colorectal cancer (CRC) patients is limited by the emergence of drug-resistant (persister) cells. Recent studies in other cancer types have shown that cells surviving initial treatment with targeted agents are often vulnerable to alterations in cell metabolism including oxidative stress. Vitamin C (VitC) is an antioxidant agent which can paradoxically trigger oxidative stress at pharmacological dose. Here we tested the hypothesis that VitC in combination with cetuximab could restrain the emergence of secondary resistance to EGFR blockade in CRC RAS/BRAF wild-type models. We found that addition of VitC to cetuximab impairs the emergence of drug persisters, limits the growth of CRC organoids, and significantly delays acquired resistance in CRC patient-derived xenografts. Mechanistically, proteomic and metabolic flux analysis shows that cetuximab blunts carbohydrate metabolism by blocking glucose uptake and glycolysis, beyond promoting slow but progressive ROS production. In parallel, VitC disrupts iron homeostasis and further increases ROS levels ultimately leading to ferroptosis. Combination of VitC and cetuximab orchestrates a synthetic lethal metabolic cell death program triggered by ATP depletion and oxidative stress, which effectively limits the emergence of acquired resistance to anti-EGFR antibodies. Considering that high-dose VitC is known to be safe in cancer patients, our findings might have clinical impact on CRC patients treated with anti-EGFR therapies.

A guide to plasma membrane solute carrier proteins

“…A recent study showed that a combinatorial therapy of doxycycline, azithromycin, and vitamin C effectively eradicates cancer stem cells [239]. Similarly, a combination treatment of vitamin C and cetuximab was recently shown to be an effective treatment to limit the development of acquired resistances in colorectal cancer, slowed the growth of cancerous cells, and impaired the structure of organoids [240].…”

The emerging role of ferroptosis in intestinal disease

“…Persister cells are clones that survive initial cancer treatment and induce drug-resistant states across diverse cancer contexts 64 , 65 . Interestingly, induction of ferroptosis can kill these drug-tolerant persister cells and decrease the emergence of acquired drug resistance 66 , 67 . In addition, the epithelial-to-mesenchymal transition (EMT) is one of the mechanisms leading to apoptotic failure and drug resistance in epithelial-derived carcinoma cells 68 .…”

“…Chen et al reported that the bioactive compound β-elemene (extracted from the Chinese herb Curcumae Rhizoma) is a ferroptosis inducer; they combined treatment with β-elemene and anti-EGFR (epidermal growth factor receptor) antibody cetuximab to produce anti-tumour effects by triggering ferroptosis in CRC patients with RAS mutations that do not respond to cetuximab 99 , 101 . Another study showed that vitamin C, an antioxidant that can paradoxically initiate oxidative stress at pharmacological doses, targeted cetuximab-persister cells and restricted the emergence of acquired resistance to EGFR blockade in CRC through the induction of ferroptosis 67 . Altogether, the role of ferroptosis in CRC in inhibiting tumour growth and overcoming resistance to current anticancer drugs is a promising avenue for research.…”

“… 99 Vitamin C DiFi cells; CRC organoids Induction Vitamin C altered iron homoeostasis, increased ROS production and triggered ferroptosis. 67 Resibufogenin HT29/SW480 cells; Orthotopic xenografts mice Induction Resibufogenin induced ferroptotic cell death in a GPX4 inactivation-dependent manner. 18 IMCA DLD-1/HCT116 cells; Orthotopic xenografts mice Induction IMCA triggered ferroptotic cell death by downregulating SLC7A11 via the AMPK/mTOR signalling pathway in CRC.…”

High-Dose Vitamin C: Preclinical Evidence for Tailoring Treatment in Cancer Patients

“…Indeed, in several tumors (e.g., KRAS/BRAF mutated colorectal, gastric, or breast cancer) the sensitivity to vitamin C correlated with the expression of GLUT1 and DHA adsorption [ 44 , 45 , 46 , 47 , 180 , 181 ]. Interestingly, the activity of vitamin C against KRAS/BRAF mutated colorectal cancer might be useful to counteract tumor resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (i.e., cetuximab, panitumumab) [ 182 ].…”