The role of methylglyoxal stress in developing acquired resistance to cetuximab in quadruple wild-type colorectal cancer

Colorectal cancer (CRC) ranks as the third most frequently diagnosed cancer, and the limited efficacy of current treatments often leads to frequent relapses. Cetuximab (CTX) stands as the most used anti-EGFR targeted therapy for CRC. Mutation of oncogenes is commonly associated with the development of resistance to CTX. However, patients with CRC classified as "quadruple wild type" (4WT), characterized by the absence of mutations in KRAS, NRAS, BRAF, and PIK3CA, also exhibit a resistance to this therapy. The dependency of cancer cells on glycolysis promotes the initiation and progression of tumors. Methylglyoxal (MG), an inevitable by-product of glycolysis, induces glycation on proteins, lipids and DNA. We have previously shown that the depletion of glyoxalase 1 (GLO1), the main MG detoxifying enzyme, induces an endogenous MG stress that enhances growth and metastatic capacity. We observed that GLO1-depleted CRC cells develop resistance to CTX. This project endeavours to elucidate the molecular mechanisms, driven by MG stress, that lead to the development of CTX resistance in 4WT cells.
The use of CRC resistant clones, generated after long term challenge with CTX, let us conclude that MG stress was not a major feature of resistant cells. Therefore, we next focused on the generation of persistent CRC cells, enriched after short challenge with CTX, to better position MG stress during the process of the acquisition of resistance. Persistent cells demonstrated resistance to CTX that was evidenced by a gain in AKT and ERK activation, efficient escape from apoptosis when compared with parental cells. Nevertheless, persistence was not associated with MG stress as shown by unchanged free MG/MG protein adducts levels and GLO1 activity.
Knowing that the sole induction of MG stress in 4WT CRC cells render them resistant to CTX resistance, we next used GLO1-depleted cells to understand how MG triggers acquired resistance. Upon MG stress and CTX challenge, resistant cells displayed enhanced EGFR activation and persistent activation of ERK/MEK pathway when compared with control cells. Taken together, these findings suggest that MG stress may facilitate cellular resistance to anti-EGFR therapy. Ongoing experiments will help demonstrating the use of MG scavengers to potentially resensitize resistant CRC cells to CTX.