Review ArticleReview
Open Access

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

Li Gong, Shixue Yang, Junli Huang and Yongsheng Li
Cancer Biology & Medicine November 2024, 20240320; DOI: https://doi.org/10.20892/j.issn.2095-3941.2024.0320

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.

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Introduction

Cancer represents a significant public health challenge globally with the rapid advance of various anti-cancer pharmacotherapies, including chemotherapy, targeted therapy, and immunotherapy. Targeted therapy, which specifically aims to eliminate tumor cells, has emerged as a valuable treatment option for many cancer patients1. The development of targeted agents focuses on the regulation of specific receptors, signal transduction pathways, neovascularization, and critical targets, such as the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and kirsten rat sarcoma viral oncogene homologue (KRAS)2,3. Nevertheless, resistance to targeted agents poses a significant clinical challenge that adversely affects treatment response and patient prognosis1. Mechanisms contributing to drug resistance include DNA damage repair, altered signaling pathways, abnormal metabolism, and the tumor microenvironment3. The limitations of single-target drugs in cancer treatment arise from the complexity of resistance mechanisms, highlighting the necessity for exploring additional strategies to enhance treatment outcomes and overcome resistance. Recent research indicates that gut microbiota and gut microbiota byproducts may have a role in influencing the efficacy and side effects of targeted therapy4,5.

The human gut microbiota, which is comprised of bacteria, archaea, and eukarya, have co-evolved with humans for centuries, establishing a complex and mutually beneficial relationship6. The gut microbiota are crucial for maintaining gut health, providing energy, metabolizing substances (such as drugs and toxins), combating pathogens, and regulating the host immune system7. In healthy individuals the gut microbiota landscape is predominantly characterized by Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Verrucomicrobia, with Firmicutes and Bacteroidetes being the principal communities8,9. While the gut microbiota have an essential role in various physiologic functions, the gut microbiota are also associated with a range of diseases, including neurodegenerative disorders10, psychological disorders11, and inflammatory disorders12. Recent research has highlighted the significant influence of the gut microbiota in cancer studies13. Notably, patients with different tumor types exhibit distinct microbiota compositions, which may contribute to tumor development and progression14,15. For example, colorectal cancer (CRC) patients have a marked increase in Fusobacterium nucleatum, Porphyromonas asaccharolytica, and Prevotella intermedia14. In contrast, breast cancer patients have a high abundance of Clostridiaceae, Faecalibacterium, and Ruminococcaceae, coupled with a reduced presence of Lachnospiraceae and Dorea16. Lung cancer patients have an elevated number of Bacteroides, Veillonella, and Fusobacterium nucleatum a lower number of Escherichia-Shigella, Kluyvera, and Fecalibacterium compared to healthy individuals17. Emerging evidence suggests that gut microbiota modulate the efficacy of chemotherapy, potentially influencing treatment outcomes in both positive and negative ways18, inducing tumor resistance to chemotherapy and immunotherapy19,20, and contributing to adverse reactions associated with anti-cancer therapies20.

This review provides a thorough analysis of the interactions between gut microbiota and gut microbiota metabolites with the EGFR, VEGF, and KRAS signaling pathways in cancer. The review presents preclinical and clinical evidence to demonstrate how gut microbiota and gut microbiota metabolic products affect the efficacy of targeted anti-cancer therapies. Furthermore, the review discusses the existing challenges in this field and proposes potential avenues for future research.

Association between the EGFR pathway and gut microbiota

Landscape of EGFR pathway

EGFR is a member of the HER family of receptor tyrosine kinases. Overexpression of EGFR, in addition to mutations, increased ligand production, and impaired receptor downregulation, is associated with tumor progression, metastasis, cell proliferation, migration, and motility21. EGFR is commonly detected in various solid tumors, such as breast cancer, and treatments targeting this receptor have demonstrated significant efficacy in clinical settings (Figure 1). Recent studies suggest a potential link between gut microbiota, the EGFR signaling pathway, and the response to anti-EGFR therapies (Figure 2C). This section consolidates key insights pertaining to the interaction between the EGFR pathway and gut microbiota.

Figure 1
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
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.

Interaction between the EGFR pathway and gut microbiota/metabolites

Bacterial phyla variations in EGFR-mutant versus EGFR-wild-type (WT) non-small cell lung cancer (NSCLC)

Woraseth et al. conducted a study on the gastrointestinal microbiota profiles of patients with EGFR-WT and EGFR-mutant advanced NSCLC. The results indicated that the five most abundant bacterial phyla across all patient groups were Proteobacteria, Bacteroidetes, Firmicutes, Fusobacteriota, and Verrucomicrobia. Notably, Proteobacteria were elevated in the EGFR-WT cohort, while Bacteroidetes and Firmicutes were more prevalent in the EGFR-mutant cohort. These bacterial populations, along with bacterial metabolites, may have a role in the carcinogenesis of NSCLC22.

Impact of gut microbiota metabolites on carcinogenesis

Gut microbiota produce metabolites within the intestinal environment that have a crucial role in the interaction between the gut microbiota and the human body23. These metabolites function as signaling molecules and substrates, regulating various biological pathways. While some metabolites exhibit protective and antineoplastic properties, other metabolites may be harmful and carcinogenic24. The composition of these metabolites encompasses sugars, lipids, proteins, peptides, amino acids, volatile small molecules, glycolipids, and organic acids25. Notably, metabolites associated with the gut microbiota include bile acids [deoxycholic acid (DCA), lithocholic acid, and ursodeoxycholic acid (UDCA)], short-chain fatty acids (acetate, propionate, and butyrate), trimethylamine n-oxide (TMAO), tryptophan derivatives (indoleacetic acid and indole), and virulence factors (FadA and Fap2; Figure 2A and B)26,27.

Dual role of bile acids in modulating EGFR signaling

DCA and UDCA are the primary secondary bile acids produced by Clostridium and Parabacteroides distasonis, respectively25. Previous studies have shown that DCA stimulates oncogene activity by activating the EGFR signaling pathway in human colon cancer cells, whereas UDCA exerts the opposite effect by inhibiting tumor progression28,29. The upregulation of EGFR activity by DCA may be attributed to promotion of epidermal growth factor (EGF) production and release, as well as disruption of membrane structure, which leads to EGFR activation28. In contrast, UDCA partially inhibits EGFR signaling through downregulation of this receptor29. Furthermore, UDCA possesses antineoplastic and apoptotic properties in bile duct cancer cells that is achieved by downregulating EGFR expression in a dose-dependent manner30. Additionally, UDCA inhibits epithelial-mesenchymal transition (EMT) and reduces the invasion of bile duct cancer cells by suppressing the EGF-EGFR pathway, which enhances E-cadherin expression while decreasing N-cadherin expression31. Notably, the anti-cancer effect of UDCA is comparable to that of gefitinib, an EGFR inhibitor, and the combination of UDCA with gefitinib may producea an additive effect on tumor cells31. Consequently, UDCA may represent a promising antineoplastic agent and a potential combination therapeutic option to enhance the efficacy of targeted anticancer treatments.

Fusobacterium nucleatum promotes EMT via activating EGFR pathway

Fusobacterium nucleatum, a significant pathogen associated with chronic periodontitis, is elevated in CRC patients32. Recent research by Mi et al. demonstrated that F. nucleatum accelerates the progression of colitis-associated cancer by promoting EMT through activation of the EGFR pathway, which involves protein kinase B (AKT) and extracellular signal-regulated kinase (ERK)33.

Collectively, gut microbiota, particularly Clostridium, Parabacteroides distasonis, and F. nucleatum, are emerging as predictive biomarkers linked to the EGFR pathway in cancer development. Targeting these microbiota and the microbiota metabolites, such as UDCA and DCA, may offer an effective strategy to enhance the outcomes of anti-EGFR therapy and prevent the onset of CRC, bile duct cancer, and NSCLC. Future research that focuses on the gut microbiota and the gut microbiota metabolites in patients could further clarify the interactions with the EGFR pathway in tumors.

Association between the VEGF pathway and gut microbiota

Landscape of the VEGF pathway

VEGF has a pivotal role in the progression of malignant tumors by facilitating angiogenesis and promoting cell migration34. Furthermore, VEGF and its receptor (VEGFR) signaling pathways contribute to the establishment of an immunosuppressive tumor microenvironment by increasing the accumulation of myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), while simultaneously inhibiting the maturation of dendritic cells (DCs)34. The overexpression of VEGF and VEGFR is a prevalent characteristic of many tumors and several inhibitors targeting these pathways are currently utilized in clinical settings (Figure 1)35. The levels of VEGF and VEGFR expression, along with the efficacy of their inhibitors, can be influenced by various factors36. Notably, the gut microbiota may have a significant role in modulating these interactions by affecting the intestinal environment and its associated metabolites.

Interaction between the VEGF pathway and gut microbiota/metabolites

DCA upregulates the VEGF pathway activity

VEGFR activation by bile acids, such as chenodeoxycholic acid, has been documented in specific neoplastic tissues37. DCA significantly upregulates VEGF mRNA expression in Barrett’s carcinoma cell lines38. Additionally, an increasing body of evidence suggests that a high-fat diet (HFD) leads to dysbiosis of the gut microbiota, resulting in prolonged intestinal exposure to DCA39.

SCFAs decrease VEGF and neuropilin-1 expression

Butyrate, a short-chain fatty acid (SCFA) and a natural histone deacetylase inhibitor (HDACi), has been shown to induce apoptosis in colon cancer cells40. The gut microbiota, which is comprised of Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, Prevotella, Propionibacterium, Faecalibacterium, Oscillospira, Ruminococcaceae, Eubacterium, and Coriobacteriaceae spp., produces SCFAs through fermentation of undigested dietary fibers in the human intestines41–43. Research indicates that butyrate decreases VEGF and neuropilin-1 (NRP-1) expression at the mRNA and protein levels in CRC cell lines40,44. NRP-1 is a crucial regulator of apoptosis and angiogenesis, functioning as a transmembrane receptor expressed in cancer and endothelial cells, where NRP-1 binds to VEGF. Butyrate inhibits NRP-1 expression by obstructing the transactivation of specificity protein 1 (Sp1) and reducing Sp1 binding affinity to the NRP-1 promoter40,44. Additionally, Sp1 is a key transcription factor that regulates VEGF expression45. Inhibition of Sp1 transcription by butyrate has a significant role in decreasing VEGF levels40.

TMAO boosts VEGF production and antitumor immunity

TMAO, a metabolite produced by the gut microbiota (specifically by Enterobacteriaceae) is a significant factor that enhances VEGF production and secretion from tumor cells and facilitates tumor angiogenesis. These effects may contribute to activation of the nuclear factor-κB (NF-κB) signaling pathway by TMAO25,46. The mechanism underlying TMAO activation of NF-κB signaling is unclear in cancer. NF-κB is the transcription regulator of pro-angiogenic factors in cancer, including VEGF, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF)47. Additionally, Wang et al. conducted a multi-omics analysis involving 360 patients with triple-negative breast cancer (TNBC) and discovered that Clostridiales, which includes Blautia, Ruminococcus, Faecalibacterium, Dorea, Tyzzerella, and Roseburia, along with its metabolite TMAO, were more prevalent in tumors characterized by an activated immune microenvironment48. Mechanistically, TMAO activates the endoplasmic reticulum stress kinase, which in turn enhances CD8+ T cell-mediated antitumor immunity in tumor cells, leading to apoptosis48. While the VEGF/VEGFR signaling pathway is known to contribute to an immunosuppressive tumor microenvironment, TMAO appears to promote antitumor immunity within the tumor.

LPS upregulates VEGF expression

Lipopolysaccharide (LPS), a microbe-associated molecular pattern (MAMP) and a gram-negative bacterial antigen, contributes to the progression of CRC49. LPS induces hepatic stellate cells to secrete various pro-angiogenic factors, including VEGF, and upregulates VEGF expression, thereby promoting angiogenesis in hepatocellular carcinoma (HCC)50,51. VEGFR, a receptor tyrosine kinase, is highly expressed in several tumor types, including CRC and HCC. Zhu et al. conducted an in vitro investigation to explore the relationship between LPS and VEGFR in the context of CRC, which revealed that LPS enhances VEGFR expression by increasing NF-κB binding to the VEGFR promoter and subsequently facilitates cellular migration and invasion52.

These findings offer new insights into a novel mechanism by which the gut microbiota and gut microbiota metabolites influence the VEGF/VEGFR signaling pathway. The interaction between the VEGF/VEGFR pathway and these metabolites is illustrated in Figure 2C. This understanding provides important strategies for modulating anti-vasculogenic mimicry therapy. A clearer comprehension of the relationship between gut microbiota-derived metabolites and the VEGF pathway may have a significant role in the management and prevention of cancers, especially CRC.

Interaction between VEGF inhibitors and antibiotics/probiotics

Antibiotic use affects VEGF-tyrosine kinase inhibitor (TKI) efficacy

A retrospective study investigated the impact of antibiotics targeting Bacteroides spp. on the progression-free survival (PFS) of patients receiving VEGF-TKIs for metastatic renal-cell carcinoma (RCC). The results indicated that patients treated with antibiotics effective against Bacteroides spp. demonstrated improved PFS53. This beneficial effect may be linked to a reduction in diarrhea associated with Bacteroides spp53. In contrast, another study proposed that antibiotic use could diminish the efficacy of TKIs in patients with advanced melanoma and NSCLC, leading to decreased PFS and overall survival (OS)54. The interaction between antibiotics and TKIs may influence pharmacokinetic properties, resulting in a shorter PFS54. Further research is required to clarify the specific mechanisms underlying the interaction between antibiotics and VEGF inhibitors.

Probiotic supplementation benefits the efficacy of VEGF-TKIs

Probiotic supplementation has the potential to modulate the composition of the intestinal microbiome. A prospective randomized study demonstrated that the administration of probiotics can increase the levels of Bifidobacterium spp. in patients with metastatic RCC55. Previous research indicated that patients with metastatic RCC undergoing VEGF-TKI treatment may exhibit reduced levels of Bifidobacterium spp. compared to healthy individuals56. The presence of Bifidobacterium spp. has been associated with favorable clinical outcomes in VEGF-TKI therapy, as evidenced by longitudinal stool specimen analyses showing increased abundance of Barnesiella intestinihominis and Akkermansia muciniphila55. Consequently, probiotic supplementation may enhance the efficacy of VEGF-TKIs.

Currently, antibiotic and probiotic treatments have demonstrated promising results as modulators of gut microbiota57. By carefully selecting antibiotic regimens that specifically target potentially harmful microbiota while promoting the growth of beneficial strains, positive outcomes in targeted therapies may be achieved. Although CRISPR-Cas9-encoding phages have been proposed for the selection of disease-associated microbiota, application in cancer treatments remains limited58. Additionally, a small-molecule approach to modulating the composition and function of gut microbiota is currently under development. These studies offer new opportunities to enhance the effectiveness of anti-cancer targeted therapies by concentrating on specific gut microbiota.

Association between KRAS pathway and gut microbiota

Landscape of KRAS pathway

The RAS oncoproteins, which are membrane-associated proteins, have a critical role in the development of human cancers59. KRAS, in particular, is a vital signaling protein that is instrumental in maintaining intestinal homeostasis and influencing both the development and progression of cancer60. The current options for targeted therapy in KRAS mutant cancers are limited, underscoring the necessity for improved treatment responses. Investigating the relationship between KRAS, gut microbiota, and metabolites, and the effects on cancer phenotype is essential for the advancement of targeted therapy strategies. This section highlights significant discoveries regarding the interplay between the KRAS pathway and gut microbiota, offering valuable insights for the development of anti-KRAS therapies.

Relationship between gut microbiota/metabolites and energy metabolism in KRAS pathway

Gut microbiota regulates glucose metabolism

The gut microbiota may influence the efficacy of KRAS inhibitors by modulating energy metabolism within the intestinal environment. An increase in Prevotella, resulting from dietary fiber intake, enhances glucose metabolism and mitigates glucose intolerance induced by Bacteroides (Figure 3A)61. Glycolysis generates adenosine triphosphate and nicotinamide adenine dinucleotide, which are essential for poly (ADP-ribose) polymerase (PARP) in repairing DNA damage and powering multidrug resistance efflux pumps that expel toxic substances. This finding suggests that heightened glycolysis may contribute to drug resistance (Figure 3B)42. Cancers harboring KRAS mutations frequently display elevated levels of glucose transporter-1 (GLUT1), a gene that encodes GLUT1 and has a crucial role in glycolysis and the reprogramming of energy metabolism (Figure 3B)62. Furthermore, glucose deprivation in tumor cells promotes the emergence of KRAS mutations62. Consequently, manipulating the gut microbiota presents a promising strategy to diminish drug resistance and enhance the effectiveness of KRAS inhibitors.

Figure 3
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.

The metabolite, conjugated linoleic acid (CLA), regulates lipid metabolism

Trans-10, cis-12 (t10, c12) CLA is a significant metabolite produced by gut microbiota and is known for its anti-colon cancer properties41,63,64. The bacterial genera, Lactobacillus, Bifidobacterium, and Roseburia, are typically responsible for the production of CLA65. Rumen bacteria contribute to the synthesis of CLA from linoleic acid through biohydrogenation and isomerization, followed by the Δ9 dehydrogenation of trans-11 vaccenic acid in mammals41. This specific type of CLA interferes with the synthesis of endogenous ligands for proliferator-activated receptor gamma (PPAR-γ) in human preadipocytes, specifically downregulating the expression of PPARγ, which reduces triglyceride accumulation and lipogenesis (Figure 3C)66. Although the exact effects of t10, c12 CLA are not fully understood, research by Go et al. suggests that gut microbiota-generated t10, c12 CLA stimulates hepatic de novo lipogenesis and triglyceride synthesis by activating the mTOR pathway (Figure 3C)67. Hepatocyte steatosis, a crucial mechanism in HCC, is influenced by gut microbiota and gut microbiota metabolites, potentially contributing to hepatocarcinogenesis68,69. Further investigation into the relationship between gut microbiota/metabolites, like CLA, and the impact on liver lipid metabolism holds promise for valuable insights.

Interaction between the PI3K/AKT/mTOR pathway and gut microbiota/metabolites

Propionate and butyrate modulate autophagy in cancer cells via the PI3K/AKT/mTOR pathway

Gut microbiota metabolites have been shown to potentially influence the response to KRAS inhibitors. Studies have indicated that propionate and butyrate hinder cell proliferation, induce apoptosis, and stimulate autophagy in various cancers by modulating the PI3K/AKT/mTOR pathway41,70,71. Specifically, propionate suppresses the mTOR signaling pathway, leading to autophagy through mTOR phosphorylation70. Conversely, butyrate triggers autophagy by increasing the generation of reactive oxygen species (ROS), which subsequently inhibits AKT phosphorylation and mTOR activity72. Additionally, research conducted by Wei et al. has emphasized that gut microbiota abundant in butyrate-producing bacteria, such as Faecalibacterium prausnitzii, can enhance the efficacy of echinacoside in suppressing the Wnt/β-catenin pathway by downregulating the PI3K/AKT/mTOR signaling cascade4.

LPS stimulates carcinogenesis by activating KRAS pathway

Conversely, LPS can hyper-stimulate KRAS, initiating carcinogenesis73. Lu et al. demonstrated that the co-expression of TWIST1a+ and KRAS+ in conjunction with LPS exposure exacerbates the development of metastatic HCC. This finding suggests that LPS may activate the progression and metastasis of HCC in cases with KRAS mutations74. The expression of KRASV12, when combined with LPS treatment, enhances intestinal tumor progression by promoting both cell apoptosis and proliferation, as well as activating the PI3K/AKT and ERK signaling pathways75. Furthermore, Xie et al. reported that LPS activates the PI3K/AKT/mTOR pathway, while inhibiting autophagy in an inflammation model76. Chronic inflammation is recognized as one of the mechanisms underlying the development of pancreatic adenocarcinoma (PDAC). Massoumi et al. analyzed the canonical pathways altered following LPS exposure in PDAC cell lines77. Massoumi et al. reported that the PI3K/AKT/mTOR pathway is the top canonical pathway affected by LPS. LPS induces the activation of the PI3K/AKT/mTOR pathway through the increased phosphorylation, which contributes to increase the invasive capacity of PDAC cells77.

Opposing roles of UDCA and DCA on KRAS signaling

The effects of DCA and UDCA on the KRAS pathway are notably distinct. UDCA has exhibited antineoplastic properties and the capacity to induce apoptosis in bile duct cancer cells by inhibiting the PI3K/AKT pathway30. Conversely, DCA activates PI3K/AKT signaling, which enhances the proliferation and invasiveness of cancer cells30. Additionally, UDCA prevents lipid accumulation and alleviates liver impairment by inhibiting the AKT/mTOR/SREBP1 pathway, indicating a promising strategy for staving off fibrosis progression in patients with HCC78. Furthermore, the combination of UDCA with an mTOR inhibitor significantly reduces tumor growth, immune evasion, and activation of the Ras signaling pathway in HCC rat models79. This research suggests that such combinations may provide clinical benefits to patients, although further validation through clinical trials is warranted.

The interaction between the PI3K/AKT/mTOR pathway and metabolites is depicted in Figure 2C. In conclusion, exploring the relationship between the KRAS pathway, gut microbiota, and metabolites could unveil new opportunities for enhancing therapeutic efficacy and overcoming resistance associated with anti-KRAS targeted therapies.

Relationship between gut microbiota and the safety of targeted therapy

Modulating gut microbiota prevents TKI-induced diarrhea

The gut microbiota have a significant role in the safety of anti-cancer treatments. Previous research has demonstrated that the addition of Lactobacillus reuteri and Clostridium butyricum can help protect against cisplatin-induced nephrotoxicity, while Lactobacillus reuteri has been shown to alleviate immunotherapy-related colitis80,81. Notably, diarrhea is the primary adverse event (AE) associated with alterations in gut microbiota during targeted treatment. The gut microbiota is increasingly recognized for its involvement in both the development and management of TKI-induced diarrhea5. A clinical trial highlighted the positive impact of fecal microbiota transplantation (FMT) on TKI-induced diarrhea in patients with metastatic renal cell carcinoma (RCC) (NCT04040712)5. FMT involves transplanting stool from a healthy donor into the intestine of another patient82. Furthermore, targeted antibiotic therapy against gram-negative bacteria has proven effective in preventing neratinib-induced diarrhea83. These findings suggest a promising strategy for managing EGFR-TKI-induced diarrhea.

Gut microbiota as the safety biomarker for EGFR-TKIs

Studies have shown that patients undergoing treatment with VEGF-TKIs and experiencing diarrhea have elevated levels of Bacteroides spp., reduced levels of Prevotella spp., and decreased levels of butyrate-producing bacteria, including Faecalibacterium, Oscillospira, Ruminococcaceae, Eubacterium, and Coriobacteriaceae43,56. Saifon et al. conducted a study to investigate the correlation between gut microbiota composition and the severity of adverse events (AEs) associated with EGFR-TKIs22. The results indicated that patients experiencing mild AEs [graded 2 according to the Common Terminology Criteria for AEs (CTCAE)] had higher levels of Proteobacteria, while patients with severe AEs (also graded 2 as per CTCAE) exhibited increased levels of Bacteroidetes and Firmicutes22. These findings may serve as potential safety biomarkers for EGFR-TKIs and could provide opportunities to target specific microbiota using techniques, such as targeted microbial-modulating therapy (e.g., FMT, probiotics, and bacteriophage) to manage TKI-related toxicity57,84.

Current research on the correlation between AEs associated with KRAS inhibitors and gut microbiota is limited. In addition to gastrointestinal toxicity, other prevalent adverse events linked to targeted agents include skin toxicity, hematologic toxicity, pulmonary toxicity, and cardiotoxicity. The relationship between gut microbiota and gut microbiota metabolites is not yet fully understood. Therefore, further studies are necessary to explore the impact of gut microbiota on the safety of targeted therapies.

Conclusions and perspectives

EGFR, VEGF, and KRAS are frequently mutated targets in a variety of cancers. Recent studies indicate that the gut microbiota, along with gut microbiota metabolites, such as BAs, SCFAs, and TMAO, influence these targets. Additionally, microbe-associated molecular interactions, such as LPS, have been shown to potentially affect cancer development and the efficacy of anti-cancer treatments (Tables 1, 2 and Figures 2, 3).

View this table:
Table 1

Gut microbiota and gut microbiota-associated metabolites in the oncogenic targeted pathways

View this table:
Table 2

Gut microbiota modulates the clinical outcome of anti-cancer targeted therapy

DCA and UDCA are BAs with contrasting effects on tumor dynamics, exhibiting pro- and anti-tumor properties, respectively. DCA, a metabolite of Clostridium sordelli, promotes tumor development by activating EGFR and the PI3K/AKT signaling pathway. Conversely, UDCA, primarily produced by Parabacteroides distasonis, counteracts the tumor-promoting effects of DCA, thereby inhibiting tumor progression. Furthermore, UDCA is recognized as a natural inhibitor of TGF-β, which may enhance immunotherapy outcomes85. These findings indicate that UDCA possesses both targeted and immunomodulatory effects. While clinical trials suggest that leveraging the gut microbiota may enhance immunotherapy, the impact on targeted therapy remains uncertain.

SCFAs, primarily butyrate and propionate, exert anti-cancer effects by reducing VEGF levels, inhibiting the phosphorylation of AKT and mTOR, and downregulating the activity of the PI3K/AKT/mTOR signaling pathway. Notable SCFA-producing bacteria include Bacteroides, Bifidobacterium, Clostridium, Lactobacillus, Prevotella, Propionibacterium, Faecalibacterium, Oscillospira, Ruminococcaceae, Eubacterium, and Coriobacteriaceae25. A decreased abundance of these bacteria has been observed in various cancers, such as lung cancer17. Therefore, regulating the populations of SCFA-producing bacteria may enhance the efficacy of targeted therapies aimed at VEGF and KRAS.

CRC is closely linked to the gut microbiota, with F. nucleatum being particularly abundant in CRC patients. F. nucleatum has been shown to promote EMT and activate EGFR signaling25,33. Additionally, LPS, a MAMP of gram-negative bacteria, has a significant role in the initiation of CRC, HCC, and PDAC52,74,77. LPS upregulates the expression of VEGFR, thereby promoting migration and invasion, while also activating the PI3K/AKT/mTOR pathway and inhibiting autophagy52,74,77. Furthermore, the gut microbiota and its metabolites have been implicated in the regulation of HCC development86,87. CLA may contribute to the pathologic mechanisms underlying HCC through activation of the mTOR pathway67,68.

The composition of gut microbiota varies with the severity of AEs induced by EGFR-TKIs. Notably, elevated levels of Bacteroidetes and Firmicutes are observed in patients experiencing severe AEs, suggesting that these gut microbiota may serve as potential biomarkers for safety monitoring22. However, there is limited data available regarding other anti-cancer targeted agents. Interventions aimed at modulating gut microbiota, such as antibiotic treatment or FMT, have shown promise in alleviating TKI-related diarrhea5,83. Furthermore, the relationship between gut microbiota and other AEs induced by targeted agents warrants further investigation, particularly concerning neurotoxicity and hematologic toxicity.

Questions remain regarding the diversity and susceptibility of gut microbiota and gut microbiota metabolites among individuals, influenced by factors such as diet, disease, and geographic region. The challenge of reaching a consensus on gut microbiota composition is exacerbated by the variety of sequencing techniques employed, including 16S rRNA gene sequencing and metagenomic sequencing. It is imperative to control for confounding variables and to adopt distinct sequencing and analytical methodologies to accurately identify key microbiota and their metabolites. The use of CRISPR-Cas9-encoding phages presents a novel strategy for selecting and modulating specific gut microbiota. While a broad range of substances can be detected in serum or feces, the sources of gut microbiota metabolites remain somewhat limited. The human gut microbiota plays a critical role in maintaining overall homeostasis88. Emerging concepts, such as the gut-liver axis, gut-brain axis, gut-lung axis, and gut-marrow axis, have been proposed to influence disease progression68,89–91, highlighting the necessity for further research into the interactions between gut microbiota and these biological systems.

The gut microbiota may interact with oncogenic pathways, including EGFR, VEGF, and KRAS, thereby influencing the activity of these targets and the response to anti-cancer targeted therapies through mechanisms involving bacteria, metabolites, or microbe-associated molecules. With the rapid advancements in this field, the gut microbiota presents a promising avenue for enhancing the efficacy and safety of anti-cancer targeted treatments.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Li Gong, Junli Huang, Yongsheng Li.

Collected the data: Li Gong, Shixue Yang.

Contributed data or analysis tools: Li Gong, Shixue Yang.

Performed the analysis: Li Gong, Shixue Yang, Yongsheng Li.

Wrote the paper: Li Gong, Shixue Yang, Junli Huang, Yongsheng Li.

  • Received August 4, 2024.
  • Accepted November 4, 2024.

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