Modulation of gut microbiota in targeted cancer therapy: insights on the EGFR/VEGF/KRAS pathways

Abstract

The rise in the incidence of cancer globally has led to a heightened interest in targeted therapies as a form of anticancer treatment. Key oncogenic targets, including epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and kirsten rat sarcoma viral oncogene homologue (KRAS), have emerged as focal points in the development of targeted agents. Research has investigated the impact of gut microbiota on the efficacy of various anticancer therapies, such as immunotherapy, chemotherapy, and radiotherapy. However, a notable gap exists in the literature regarding the relationship between gut microbiota and targeted agents. This review emphasizes how specific gut microbiota and gut microbiota metabolites, including butyrate, propionate, and ursodeoxycholic acid, interact with oncogenic pathways to modulate anti-tumor effects. Conversely, deoxycholic acid, lipopolysaccharide, and trimethylamine n-oxide may exert pro-tumor effects. Furthermore, modulation of the gut microbiota influences glucose and lipid metabolism, thereby enhancing the response to anti-KRAS agents and addressing diarrhea induced by tyrosine kinase inhibitors. By elucidating the connection between gut microbiota and the EGFR/VEGF/KRAS pathways, this review provides valuable insights for advancing targeted cancer therapy and optimizing treatment outcomes in clinical settings.

Keywords: EGFR; Gut microbiota; KRAS; VEGF; metabolites; targeted therapy; tumorigenesis pathway.

Figure 1

The approved drugs targeting EGFR/VEGF/KRAS mutations in cancers. NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; HCC, hepatocellular carcinoma; HNC, head and neck cancer; RCC, renal cell carcinoma; CRC, colorectal cancer; STS, soft tissue sarcoma.

Figure 2

Relationships between gut microbiota, gut microbiota-associated metabolites, and EGFR/VEGFR/KRAS pathways. (A) Gut microbiota and gut microbiota-associated metabolites. (B) The bacteria produce special products. *SCFAs-producing bacteria include Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, Prevotella, Propionibacterium, Faecalibacterium, Oscillospira, Ruminococcaceae, Eubacterium, and Coriobacteriaceae. **SCFAs primarily include butyrate and propionate. ***Gram-negative bacteria, especially Enterobacteriaceae and Escherichia coli. (C) The products regulate the EGFR/VEGFR/KRAS pathways. (1) UDCA downregulates EGFR expression and inhibits the PI3K/AKT pathway, thereby inducing apoptosis in tumor cells. Additionally, UDCA supresses EMT in tumor cells by inhibiting the EGF-EGFR pathway. (2) Butyrate reduces the expression of VEGF and NRP-1 by inhibiting the transactivation of Sp1 in tumor cells, which subsequently suppresses angiogenesis. Furthermore, butyrate enhances the production of ROS, leading to the inhibition of the PI3K/AKT/mTOR signaling pathway and ultimately resulting in autophagy of tumor cells. (3) Propionate inhibits the mTOR signaling pathway, contributing to autophagy in tumor cells. (4) DCA stimulates the production and release of EGF, disrupts membrane structure to upregulate EGFR activity, and activates the PI3K/AKT/mTOR pathway in tumor cells, promoting proliferation and invasiveness. DCA additionally increases the expression of VEGF mRNA in tumor cells, further enhancing angiogenesis. (5) TMAO enhances the production and secretion of VEGF from tumor cells, promoting tumor angiogenesis; the activation of NF-κB signaling by TMAO may contribute to these effects. (6) Fusobacterium nucleatum promotes EMT through the activation of the EGFR signaling pathway in tumor cells, including the downstream effector kinases AKT and ERK. (7) LPS upregulates the expression of VEGFR by enhancing NF-κB binding to the VEGFR promoter in endothelial cells, promoting tumor angiogenesis. LPS also induces the activation of the PI3K/AKT/mTOR pathway in tumor cells through increased phosphorylation, thereby enhancing the invasive ability. BAs, bile acids; DCA, deoxycholic acid; UDCA, ursodeoxycholic acid; TMAO, trimethylamine n-oxide; LPS, lipopolysaccharide; FadA, Fusobacterium nucleatum adhesin A; ROS, reactive oxygen species; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; SCFAs, short-chain fatty acids; EMT, epithelial-mesenchymal transition; NRP-1, neuropilin-1; NF-κB, nuclear factor-κB; Sp1, specificity protein 1; AKT, protein kinase B; ERK, extracellular signal-regulated kinase; P, phosphorylation.

Figure 3

Relationship between gut microbiota/metabolites and energy metabolism in KRAS pathway. (A) Intake of dietary fiber can increase Prevotella levels, potentially improving glucose metabolism and mitigating glucose intolerance. (B) Cancers with KRAS mutations exhibit upregulated GLUT1 expression. Glycolysis produces ATP and NADH, which are crucial for PARP-mediated DNA repair and for supplying energy to efflux pumps that eliminate harmful substances. (C) Trans-10,cis-12 CLA downregulates PPAR-γ and activates the mTOR pathway, thereby modulating lipid metabolism. ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide; PARP, poly (ADP-ribose) polymerase; PPAR-γ, peroxisome proliferator-activated receptor gamma; GLUT1, glucose transporter-1.