Therapeutic Approach of KRAS Mutant Tumours by the Combination of Pharmacologic Ascorbate and Chloroquine

Abstract

The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely involved in the initiation of Warburg metabolism. Although mTOR (mammalian target of rapamycin), a well-known inhibitor of autophagy-dependent survival in physiological conditions, is also activated in KRAS mutants, many recent studies have revealed that autophagy becomes hyper-active in KRAS mutant cancer cells. In the present study, a mathematical model was built containing the main elements of the regulatory network in KRAS mutant cancer cells to explore the further possible therapeutic strategies. Our dynamical analysis suggests that the downregulation of KRAS, mTOR and autophagy are crucial in anti-cancer therapy. PKM2 has been assumed to be the key switch in the stress response mechanism. We predicted that the addition of both pharmacologic ascorbate and chloroquine is able to block both KRAS and mTOR pathways: in this case, no GLUT1 expression is observed, meanwhile autophagy, essential for KRAS mutant cancer cells, is blocked. Corresponding to our system biological analysis, this combined pharmacologic ascorbate and chloroquine treatment in KRAS mutant cancers might be a therapeutic approach in anti-cancer therapies.

Crosstalk between Epigenetics and Metabolic Reprogramming in Metabolic Dysfunction-Associated Steatotic Liver Disease-Induced Hepatocellular Carcinoma: A New Sight

“…Quantitative systems pharmacology (QSP) model-based drug transformation research is an emerging international cutting-edge drug development paradigm [ 244 ]. Several mature QSP models have been developed and put into the study of glucose metabolism and the Warburg effect, changing the shortcomings of previous clinical pharmacological models lacking mechanisms [ 245 ]. Various emerging technologies based on genomics and metabolomics have also come to the fore in the study of tumor heterogeneity, cancer clone evolution, and hepatocyte network, which are undoubtedly powerful tools for understanding MASLD-HCC metabolic reprogramming deeply [ 246 , 247 ].…”

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

“…Even though PKM2 activates the mTOR pathway resulting in a block in autophagy in KRAS mutants. Autophagy is hyperactive in KRAS mutant cancer cells [ 344 ]. M Morita used KRAS in PKM2 mutant lung cancer mouse models (Kras G12D or Kras G12V ) and in SCLC cells [ 345 ].…”

Regulation of Autophagy via Carbohydrate and Lipid Metabolism in Cancer

“…Although PKM2 activates the mTOR pathway resulting in a block in autophagy in KRAS mutants. Autophagy is hyperactive in KRAS mutant cancer cells [345]. M Morita used in PKM2 mutant lung cancer mouse models (KRASG12D or KRASG12V) and in SCLC cells [346].…”