Targeting KRAS: from metabolic regulation to cancer treatment

Abstract

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the role of metabolic alterations in KRAS-driven cancers, providing a scientific rationale for targeting metabolism in cancer treatment. The development of KRAS-specific inhibitors has also garnered considerable attention, partly due to the challenge of acquired treatment resistance. Here, we review the metabolic reprogramming of glucose, glutamine, and lipids regulated by oncogenic KRAS, with an emphasis on recent insights into the relationship between changes in metabolic mechanisms driven by KRAS mutant and related advances in targeted therapy. We also focus on advances in KRAS inhibitor discovery and related treatment strategies in colorectal, pancreatic, and non-small cell lung cancer, including current clinical trials. Therefore, this review provides an overview of the current understanding of metabolic mechanisms associated with KRAS mutation and related therapeutic strategies, aiming to facilitate the understanding of current challenges in KRAS-driven cancer and to support the investigation of therapeutic strategies.

Keywords: Cancer metabolism; KRAS inhibitors; KRAS-driven cancers; Metabolic reprogramming.

Fig. 1

KRAS proteins and metabolic pathways affected by oncogenic KRAS mutation. A Illustration for the KRAS splicing variants, KRAS4A and KRAS4B. B KRAS protein structure, including the P-loop, Switch I, Switch II, and HVR. C Mechanisms of KRAS activation. D Glucose, glutamine, and lipid metabolism pathways affected by oncogenic KRAS. Oncogenic KRAS enhances glycolysis by upregulating the expression of GLUTs, which increases glucose uptake. This glucose is subsequently phosphorylated to G6P by HK1/2. G6P then enters the PPP, producing NADPH and ribose-5-phosphate essential for nucleotide synthesis. In addition, G6P is directed into the HBP, generating UDP-GlcNAc, a critical substrate for protein glycosylation. During the last stage of glycolysis, LDH converts pyruvate to lactate. KRAS mutation enhances glutamine uptake and its conversion to glutamate by GLS, which feeds into the TCA cycle. This metabolic shift involves the downregulation of GDH and upregulation of GOT, facilitating aspartate export and its conversion to NADPH via malic enzyme 1, supporting nucleotide biosynthesis and redox balance. Lipid metabolism is reprogrammed in KRAS-mutant cancer cells, with increased activation of ACS, promoting lipid biosynthesis, uptake, storage, and degradation. KRAS mutations also promote autophagy by modulating the AMPK-mTOR signaling axis, which senses nutrient availability and regulates autophagic processes, further supporting the tumor’s metabolic demands. Glu, glucose; GLUT, glucose transporter; HK1/2, hexokinase 1 and 2; G6P, glucose-6-phosphate; PPP, pentose phosphate pathway; GPL1, Glucagon-like peptide 1; F6P, Fructose-6-Phosphate; HBP, hexosamine biosynthetic pathway; UDP-GlcNAc, uridine diphosphate N-acetylglucosamine; FBP, Fructose-1,6-bisphosphatase; Gln, Glutamine; SLC25, Solute Carrier Family 25; Glu, Glutamic Acid; GDH, Glutamate Dehydrogenase; GOT2, Glutamic-Oxaloacetic Transaminase 2; Asp, Aspartic Acid; OAA, Oxaloacetic Acid; α-KG, Alpha-Ketoglutarate; IDH2, Isocitrate Dehydrogenase 2; GSH, Glutathione; GLS1, Glutaminase 1; PDH, Pyruvate Dehydrogenase; SCD1, Stearoyl-CoA Desaturase 1; ACS, Acyl-CoA Synthetase; FASN, Fatty Acid Synthase; CPT1, Carnitine Palmitoyltransferase 1; ELOVL, Elongation of Long Chain Fatty Acids; FADS1/2, Fatty Acid Desaturase 1 and 2; MUFAs, Monounsaturated Fatty Acids; PUFAs, Polyunsaturated Fatty Acids; COX-2, Cyclooxygenase 2; PGE2, Prostaglandin E2; ACC, Acetyl-CoA Carboxylase; ACLY, ATP Citrate Lyase; PI3K, Phosphoinositide-3 Kinase; AKT, Protein Kinase B; mTOR, Mammalian Target of Rapamycin; RAF, Rapidly Accelerated Fibrosarcoma Kinase; MEK, Mitogen-Activated Protein Kinase Kinase; ERK, Extracellular Signal-Regulated Kinase

Fig. 2

Targeting metabolic pathways in oncogenic KRAS-driven tumors. The circle represents a positive effect, and the triangle represents a positive or negative effect

Fig. 3

Summary of current clinical trials of KRAS inhibitors. Clinical trials of KRAS inhibitors registered on Clinicaltrials.gov (retrieved in Nov. 2024) with a particular focus on their application in treating NSCLC, PDAC, and CRC, alone or with other cancer types. Terminated or withdrawn trials are not included. Trial status: A, active but not recruiting; R, recruiting; C, completed; U, unknown status