Role of methylglyoxal stress in acquired resistance to EGFR-targeted therapy in quadruple wild-type colorectal cancer:

Colorectal cancer (CRC) is the third most common cancer diagnosed and the lack of effectiveness of current therapies leads to frequent relapses. Monoclonal antibodies cetuximab and panitumumab are the most used anti-EGFR targeted therapy in CRC. Genetic alterations, such as activating mutations, are commonly associated with a lack of response to anti-EGFR therapy. Strikingly, patients with CRC diagnosed as "quadruple wild type" (unmutated for KRAS, NRAS, BRAF and PIK3CA) also show a lack of response to this therapy. Reliance of cancer cells on glycolysis promotes tumorigenesis and malignant progression. Methylglyoxal (MG) is an unavoidable glycolytic by-product that glycates proteins, lipids, and DNA. MG stress results from the imbalance between MG production and its enzymatic detoxification by glyoxalase 1 (GLO1). Upon MG stress, cancer cells enhanced their growth and metastatic potential. In our hands, induction of MG stress in quadruple WT cells rendered them resistant to cetuximab. In this project, we aim to explore MG stress-driven molecular mechanisms underlying the acquisition of cetuximab resistance in quadruple WT CRC. Indeed, such resistant tumours could benefit from the targeting of MG stress using potent MG scavengers, such as carnosine and metformin. We have previously shown that LIM1215 human quadruple WT CRC cells undergo a glycolytic switch associated with MG stress upon the acquisition of cetuximab resistance. GLO1-depleted LIM1215 cells showed an increased viability when challenged with cetuximab. Consistently, NOD-SCID mice sub-cutaneously injected with GLO1-depleted LIM1215 cells developed cetuximab resistant tumours. We aim to use patient-derived xenograft and organoids generated from quadruple WT CRC patients to demonstrate: (1) the occurrence of MG stress and (2) the potential anti-cancer effects of MG scavengers. Mechanistically, we will consider the mutagenic potential of MG on specific oncogenic drivers of CRC, and/or the glycation of specific proteins, such as transcription factors and signalling pathway effectors, known to be implicated in CRC initiation and progression. In summary, this study will highlight the importance of the glycolytic switch in resistance to EGFR targeted therapy in quadruple WT CRC.