Methylglyoxal Scavengers Resensitize KRAS-Mutated Colorectal Tumors to Cetuximab

Abstract

Highlights d Glycolytic mutant KRAS display higher MGO stress than wildtype CRC cells d MGO stress is a potent inducer of AKT signaling in CRC cells d MGO stress induces resistance to anti-EGFR therapy in a wild-type KRAS setting d Carnosine, an MGO scavenger, sensitizes mutant KRAS CRC tumors to anti-EGFR therapy

Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress

“…Therefore, from an etiological perspective, the dramatic effect of T1DM on PDAC onset is consistent with the recent epidemiological finding that pancreatic cancer incidence increases linearly with increasing fasting glucose levels, even in populations with normal glucose range [36]. From a mechanistic perspective, and in agreement with previous studies indicating that RCS play a critical role in cancer growth [129,[159][160][161][165][166][167], treatment of diabetic mice with the carbonyl trapping agent (and AGE inhibitor) FL-926-16 prevented the accelerating effect of diabetes on PanINs progression to PDAC [203] (Figure 6). Despite the bulk of evidence indicating a role of RAGE in PDAC, only one study [171] investigated the effects of their natural ligands AGEs on RAGE activity and PDAC development (Table 1).…”

“…Based on the currently available experimental data, L-carnosine and its derivatives have proven effective in countering cancer progression, aggressiveness, and therapeutic resistance [129,160,161,167] and in preventing the PDAC-promoting effect of diabetes [203]. Altogether, these findings support the concept that carbonyl stress is critical in cancer development and growth and represents the mechanistic driver between diabetes and PDAC, mainly by favoring PanIN progression.…”

“…Consistently, YAP activation was associated with enhanced growth and metastatic potential in vivo [129]. To further confirm the causative role of the carbonyl stress-related compound MGO, all these and other effects, including resistance to epithelial growth factor receptor (EGFR)-targeted therapy in colorectal tumors [161], were reversed by using the RCS trapping agent L-carnosine [129,160,161]. Similar findings on the favorable effect of MGO-mediated protein modifications in cancer progression were previously reported in lung [165] and gastrointestinal [166] cancers and were associated with the formation of MGO-derived AGE structures on heat-shock protein 27 (Hsp27) [165,166].…”

“…Noteworthy, Bellahcène's group recently demonstrated that accumulation of AGEs is a common feature of breast cancer [129,159] and that MGOmediated glycation promotes breast cancer progression and invasiveness by inducing extracellular matrix remodeling and the activation of signaling pathways promoting survival and migration [160]. In addition, MGO stress was identified as a constant feature of KRAS-mutated colorectal tumors [161], and RCS/AGE accumulation was also found in melanoma tissues [162]. Mechanistically, MGO was demonstrated to affect heat-shock protein 90 (Hsp90) chaperone activity by inducing post-translational modification of several lysine and arginine residues, leading to the formation of the AGEs carboxyethyllysine and argpyrimidine/hydroimidazolone adducts.…”

The Dual-Role of Methylglyoxal in Tumor Progression – Novel Therapeutic Approaches

“…Moreover, Bellier et al demonstrated that the combined use of carnosine with cetuximab increases the apoptosis of KRASmutated CRC cells, unlike cetuximab treatment alone that has no effect. This effect has been also confirmed in vivo in mouse models (115).…”