Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers

Abstract

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) gain a novel function for the conversion of α-ketoglutarate (α-KG) to oncometabolite R-2-hydroxyglutarate (R-2-HG). Two molecular entities namely enasidenib (AG-221) and ivosidenib (AG-120) targeting mIDH2 and mIDH1 respectively, have already been approved by FDA for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML). However, the low responses, drug-related adverse effects, and most significantly, the clinically-acquired resistance of AG-221 and AG-120 has shown great influence on their clinical application. Therefore, searching for novel therapeutic strategies to enhance tumor sensitivity, reduce drug-related side effects, and overcome drug resistance have opened a new research field for defeating IDH-mutated cancers. As the effective methods, synthetic lethal interactions and synergetic therapies are extensively investigated in recent years for the cure of different cancers. In this review, the molecules displaying synergetic effects with mIDH1/2 inhibitors, as well as the targets showing relevant synthetic lethal interactions with mIDH1/2 are described emphatically. On these foundations, we discuss the opportunities and challenges for translating these strategies into clinic to combat the defects of existing IDH inhibitors.

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…Some metabolically altered SLIs have been revealed in IDHmutated GBM and used to treat GBM with IDH wildtype. 144,145 Studies have shown that branched-chain amino acid transaminase 1 (BCAT1) is selectively upregulated in GBM and can promote cancer growth. A metabolic synthetic lethal screen has also found that BCAT1 has a synergistic lethal effect with alphaketoglutarate (AKG).…”

“…Understanding an enhanced requirement for nutrients during carcinogenesis has been an essential underpinning of the development of modern anticancers based on therapeutics' synthetically lethal vulnerabilities. Some metabolically altered SLIs have been revealed in IDH‐mutated GBM and used to treat GBM with IDH wildtype 144,145 . Studies have shown that branched‐chain amino acid transaminase 1 (BCAT1) is selectively upregulated in GBM and can promote cancer growth.…”

Intelligent Delivery Systems in Tumor Metabolism Regulation: Exploring the Path Ahead

“…This underscores the intimate connection between tumor metabolism and epigenetics, and further insights into this relationship may hold significant therapeutic implications. [22] Comprehensive reviews on this topic have been published elsewhere. [23,24] Glutamine is converted to glutamate in the mitochondria via two forms of glutaminase within the cell: kidney-type glu-taminase1 (GLS1) and liver-type GLS2, which is a crucial first and rate-limiting step in glutamine breakdown, with downstream implications for various pathways, making it an attractive drug target.…”

“…This underscores the intimate connection between tumor metabolism and epigenetics, and further insights into this relationship may hold significant therapeutic implications. [ 22 ] Comprehensive reviews on this topic have been published elsewhere. [ 23,24 ]…”

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer

“…IDH2 is the key rate-limiting enzyme in the TCA cycle and catalyzes the conversion of isocitrate to α-KG. Cancer cells show a functional mutation in IDH2 (Yao et al, 2021). Enasidenib, an IDH2 inhibitor, is undergoing phase 1b/2 clinical trials in multiple countries.…”