Wild-type IDH1 inhibition enhances chemotherapy response in melanoma

Abstract

Background Alternative treatment strategies in melanoma beyond immunotherapy and mutation-targeted therapy are urgently needed. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme protects cancer cells under metabolic stress, including nutrient limited conditions in the tumor microenvironment. Specifically, IDH1 generates NADPH to maintain redox homeostasis and produces α-ketoglutarate to support mitochondrial function through anaplerosis. Herein, the role of wtIDH1 in melanoma is further explored. Methods The expression of wtIDH1 was determined by qRT-PCR, and Western blot in melanoma cell lines and the effect of wtIDH1 on metabolic reprogramming in melanoma was interrogated by LC-MS. The impact of wtIDH1 inhibition alone and in combination with chemotherapy was determined in cell culture and mouse melanoma models. Results Melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Thus, similar findings were replicated in murine models of melanoma. In light of the impact of wtIDH1 inhibition on oxidative stress, enzyme blockade was synergistic with conventional anti-melanoma chemotherapy in pre-clinical models. Conclusions These results demonstrate the clinical potential of wtIDH1 inhibition as a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Graphical Abstract Schematic shows increased wild-type IDH1 expression and activity as an adaptive response to metabolic stress induced by chemotherapy.

Unraveling the tumor-promoting role of wildtype Isocitrate dehydrogenase 1 (IDH1) in human gliomas

“…Moreover, wildtype IDH1 is negatively correlated with DNA damage. Previous studies reported that wildtype IDH1 was involved in tumor chemoresistance (14,25,26). However, the role of wildtype IDH1 in radioresistance has not been reported.…”

“…Wildtype IDH1 promotes the proliferation of colon cancer and renal cell carcinoma (15,16), the migration of primary GBM (17), the stemness of NSCLC (14), and the chemoresistance of melanoma, pancreatic cancer and NSCLC (14,25,26). However, the biological functions of wildtype IDH1 in tumor are still not well elucidated.…”

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation

“…Our data suggest that inhibition of wildtype IDH1, depletion of αKG through glutamine restriction, or inhibition of carnitine synthesis may act as a novel therapeutic approach in these cancers. There is evidence in other cancer types that point towards using wildtype IDH1 inhibition in combination with chemotherapy as a strategy for treatment, although these studies focused on redox balance and ROS (Vaziri-Gohar et al, 2022; Zarei et al, 2022; Zarei et al, 2023). Glutamine starvation (or glutaminase inhibition) has also been shown to have similar effects, due in part to decreased GSH and redox imbalance (Gross et al, 2014; Guo et al, 2021; Mukhopadhyay et al, 2020).…”

Comparison with gastric cancer-associated genes reveals the role of ferroptosis-related genes in eosinophils of asthma patients: A bioinformatic study

“…[ 52 ] G6PD and IDH1 maintain GSH levels by promoting NADPH generation. [ 53 , 54 ] As a member of glutathione peroxidases, GPX2 also uses GSH in antioxidant response. [ 55 ] Otherwise, it could inhibit apoptosis and promote the growth of established cancers.…”