Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model

Pagan, Beatriz; Isidro, Angel A.; Cruz, Myrella L.; Ren, Yuan; Coppola, Domenico; Wu, Jie; Appleyard, Caroline B.

doi:10.3748/wjg.v17.i44.4858

Cited by 11 publications

(5 citation statements)

References 22 publications

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“…Antitumor activity of ERL also has been reported in preclinical models of colorectal cancer (22)(23)(24). Consistent with Wingless-related integration site (WNT) plus ERK pathway interaction (25,26), WNT, EGFR, and prostaglandin E2 (PGE2)-related genes were identified as mechanistic targets modulated in patients with FAP taking ERLþSUL (27).…”

Section: Introductionsupporting

confidence: 55%

Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP)

Ulusan

Rajendran

Dashwood

et al. 2021

Cancer Prevention Research

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A clinical trial in patients with familial adenomatous polyposis (FAP) demonstrated that sulindac plus erlotinib (SUL+ERL) had good efficacy in the duodenum and colon, but toxicity issues raised concerns for long-term prevention. We performed a biomarker study in the polyposis in rat colon (Pirc) model, observing phosphorylated Erk inhibition in colon polyps for up to 10 days after discontinuing ERL+SUL administration. In a follow-up study lasting 16 weeks, significant reduction of colon and small intestine (SI) tumor burden was detected, especially in rats given 250 ppm SUL in the diet plus once-a-week intragastric dosing of ERL at 21 or 42 mg/kg body weight (BW). A long-term study further demonstrated antitumor efficacy in the colon and SI at 52 weeks, when 250 ppm SUL was combined with once-a-week intragastric administration of ERL at 10, 21, or 42 mg/kg BW. Tumor-associated matrix metalloproteinase-7 (Mmp7), tumor necrosis factor (Tnf), and early growth response 1 (Egr1) were decreased at 16 weeks by ERL+SUL, and this was sustained in the long-term study for Mmp7 and Tnf. Based on the collective results, the optimal dose combination of ERL 10 mg/kg BW plus 250 ppm SUL lacked toxicity, inhibited molecular biomarkers, and exhibited effective antitumor activity. We conclude that switching from continuous to once-per-week ERL, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care SUL against adenomatous polyps in the colon and SI, with clinical relevance for patients with FAP before or after colectomy. Prevention Relevance: This investigation concludes that switching from continuous to once-per-week erlotinib, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care sulindac against adenomatous polyps in the colon and small intestine, with clinical relevance for patients with FAP before or after colectomy.

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Section: Introductionsupporting

confidence: 55%

Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP)

Ulusan

Rajendran

Dashwood

et al. 2021

Cancer Prevention Research

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“…Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model (409). Either a selective COX-2 inhibitor (celecoxib) or a selective EGFR inhibitor (erlotinib) markedly reduced both the number and size of small intestinal adenomas in Apc ϩ/min mice, and combined treatment with both celecoxib and erlotinib almost eliminated adenoma formation (61).…”

Section: Egfr In Gi Tumorigenesismentioning

confidence: 99%

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Chen

Zeng

Forrester

et al. 2016

Physiological Reviews

209

156

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The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.

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“…These two domains are separated by a cleft, which has been found to bind ATP, ATP analogues, and ATP inhibitors in previous studies ( Stamos et al, 2002 ). Previous experimental studies of colitis showed that EGFR may regulate inflammatory cytokine production ( Lu et al, 2014 ; El Mahdy et al, 2023 ), and that the EGFR inhibitor, erlotinib, protects from chronic inflammation and development of dysplasia ( Pagán et al, 2011 ). However, some studies show that EGFR activation may also protect from colitis-associated cancer ( Dubé et al, 2012 ; Dubé et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Casuarina glauca branchlets’ extract as a potential treatment for ulcerative colitis: chemical composition, in silico and in vivo studies

Mohamed,

El-Shafae,

Fikry

et al. 2023

Front. Pharmacol.

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Ulcerative colitis (UC) is an inflammatory bowel disease that is often resistant to current treatment options, leading to a need for alternative therapies. Herbal products have shown promise in managing various conditions, including UC. However, the potential of Casuarina glauca branchlets ethanolic extract (CGBRE) in treating UC has not been explored. This study aimed to analyze the chemical composition of CGBRE and evaluate its efficacy in UC treatment through in silico and in vivo experiments. LC-ESI-MS/MS was used to identify 86 compounds in CGBRE, with 21 potential bioactive compounds determined through pharmacokinetic analysis. Network pharmacology analysis revealed 171 potential UC targets for the bioactive compounds, including EGFR, LRRK2, and HSP90 as top targets, which were found to bind to key CGBRE compounds through molecular docking. Molecular docking findings suggested that CGBRE may be effective in the prevention or treatment of ulcerative colitis mediated by these proteins, where key CGBRE compounds exhibited good binding affinities through formation of numerous interactions. In vivo studies in rats with acetic acid-induced UC demonstrated that oral administration of 300 mg/kg CGBRE for 6 days reduced UC symptoms and colonic expression of EGFR, LRRK2, and HSP90. These findings supported the therapeutic potential of CGBRE in UC and suggested the need for further preclinical and clinical investigation.

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Erlotinib inhibits progression to dysplasia in a colitis-associated colon cancer model

Abstract: Erlotinib can decrease the development of colitis-associated dysplasia, suggesting a potential therapeutic use for erlotinib in patients with long-standing colitis.

Cited by 11 publications

References 22 publications

Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP)

Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP)

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Casuarina glauca branchlets’ extract as a potential treatment for ulcerative colitis: chemical composition, in silico and in vivo studies

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