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Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model

Cancer Chemotherapy and Pharmacology volume 83, pages 531–543 (2019)Cite this article

Abstract

Purpose

Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology.

Methods

Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot.

Results

Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot).

Conclusion

Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.

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References

  1. Cherian MA, Ma CX (2017) The role of neratinib in HER2-driven breast cancer. Future Oncol 13 (22):1931–1943. https://doi.org/10.2217/fon-2017-0186 (Epub ahead of print)

    Article  CAS  Google Scholar 

  2. Kourie HR, El Rassy E, Clatot F, de Azambuja E, Lambertini M (2017) Emerging treatments for HER2-positive early-stage breast cancer: focus on neratinib. Onco Targets Ther 10:3363–3372. https://doi.org/10.2147/ott.s122397

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Echavarria I, Lopez-Tarruella S, Marquez-Rodas I, Jerez Y, Martin M (2017) Neratinib for the treatment of HER2-positive early stage breast cancer. Expert Rev Anticancer Ther 17(8):669–679. https://doi.org/10.1080/14737140.2017.1338954

    Article  PubMed  CAS  Google Scholar 

  4. Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M (2016) Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 17(3):367–377. https://doi.org/10.1016/s1470-2045(15)00551-3

    Article  PubMed  CAS  Google Scholar 

  5. Park JW, Liu MC, Yee D, Yau C, van ‘t Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA (2016) Adaptive randomization of neratinib in early breast cancer. N Engl J Med 375(1):11–22. https://doi.org/10.1056/NEJMoa1513750

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Hurvitz S, Chan A, Iannotti N, Ibrahim E, Chien J, Chan N, Kellum A, Hansen V, Marx G, Kendall SD, Wilkinson M, Castrellon A, Ruiz R, Fang P, Hunt D, Moran S, Olek E, Barcenas CH (2017) Rugo HS Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2 + early-stage breast cancer: the control trial. In: San Antonio Breast Cancer Summit, San Antonio

  7. McQuade RM, Stojanovska V, Abalo R, Bornstein JC, Nurgali K (2016) Chemotherapy-induced constipation and diarrhea: pathophysiology, current and emerging treatments. Front Pharmacol 7:414. https://doi.org/10.3389/fphar.2016.00414

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Upadhyay A, Bodar V, Malekzadegan M, Singh S, Frumkin W, Mangla A, Doshi K (2016) Loperamide Induced Life Threatening Ventricular Arrhythmia. Case Rep Cardiol 2016:5040176. https://doi.org/10.1155/2016/5040176

    PubMed  PubMed Central  Article  Google Scholar 

  9. Marraffa JM, Holland MG, Sullivan RW, Morgan BW, Oakes JA, Wiegand TJ, Hodgman MJ (2014) Cardiac conduction disturbance after loperamide abuse. Clin Toxicol (Phila) 52(9):952–957. https://doi.org/10.3109/15563650.2014.969371

    Article  CAS  Google Scholar 

  10. Karthaus M, Ballo H, Abenhardt W, Steinmetz T, Geer T, Schimke J, Braumann D, Behrens R, Behringer D, Kindler M, Messmann H, Boeck HP, Greinwald R, Kleeberg U (2005) Prospective, double-blind, placebo-controlled, multicenter, randomized phase III study with orally administered budesonide for prevention of irinotecan (CPT-11)-induced diarrhea in patients with advanced colorectal cancer. Oncology 68(4–6):326–332. https://doi.org/10.1159/000086971

    Article  PubMed  CAS  Google Scholar 

  11. Kwapisz L, Jairath V, Khanna R, Feagan B (2017) Pharmacokinetic drug evaluation of budesonide in the treatment of Crohn’s disease. Expert Opin Drug Metab Toxicol 13(7):793–801. https://doi.org/10.1080/17425255.2017.1340454

    Article  PubMed  CAS  Google Scholar 

  12. Stein A, Voigt W, Jordan K (2010) Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther Adv Med Oncol 2(1):51–63. https://doi.org/10.1177/1758834009355164

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Martinez-Moya P, Ortega-Gonzalez M, Gonzalez R, Anzola A, Ocon B, Hernandez-Chirlaque C, Lopez-Posadas R, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F (2012) Exogenous alkaline phosphatase treatment complements endogenous enzyme protection in colonic inflammation and reduces bacterial translocation in rats. Pharmacol Res 66(2):144–153. https://doi.org/10.1016/j.phrs.2012.04.006

    Article  PubMed  CAS  Google Scholar 

  14. Beigel F, Teich N, Howaldt S, Lammert F, Maul J, Breiteneicher S, Rust C, Goke B, Brand S, Ochsenkuhn T (2014) Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn’s disease: a randomized, double-blind, placebo-controlled study. J Crohns Colitis 8(11):1471–1479. https://doi.org/10.1016/j.crohns.2014.05.009

    Article  PubMed  Google Scholar 

  15. Bowen JM, Mayo BJ, Plews E, Bateman E, Stringer AM, Boyle FM, Finnie JW, Keefe DM (2012) Development of a rat model of oral small molecule receptor tyrosine kinase inhibitor-induced diarrhea. Cancer Biol Ther 13(13):1269–1275. https://doi.org/10.4161/cbt.21783

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Howarth GS, Francis GL, Cool JC, Xu X, Byard RW, Read LC (1996) Milk growth factors enriched from cheese whey ameliorate intestinal damage by methotrexate when administered orally to rats. J Nutr 126(10):2519–2530

    Article  PubMed  CAS  Google Scholar 

  17. Wardill HR, Gibson RJ, Van Sebille YZ, Secombe KR, Coller JK, White IA, Manavis J, Hutchinson MR, Staikopoulos V, Logan RM, Bowen JM (2016) Irinotecan-induced gastrointestinal dysfunction and pain are mediated by common TLR4-dependent mechanisms. Mol Cancer Ther 15(6):1376–1386. https://doi.org/10.1158/1535-7163.mct-15-0990

    Article  PubMed  CAS  Google Scholar 

  18. Boue S, Fortgang I, Levy RJ Jr, Bhatnagar D, Burow M, Fahey G, Heiman ML (2016) A novel gastrointestinal microbiome modulator from soy pods reduces absorption of dietary fat in mice. Obesity (Silver Spring) 24(1):87–95. https://doi.org/10.1002/oby.21197

    Article  CAS  Google Scholar 

  19. Sann H, Erichsen J, Hessmann M, Pahl A, Hoffmeyer A (2013) Efficacy of drugs used in the treatment of IBD and combinations thereof in acute DSS-induced colitis in mice. Life Sci 92(12):708–718. https://doi.org/10.1016/j.lfs.2013.01.028

    Article  PubMed  CAS  Google Scholar 

  20. Ocon B, Aranda CJ, Gamez-Belmonte R, Suarez MD, Zarzuelo A, Martinez-Augustin O, Sanchez de Medina F (2016) The glucocorticoid budesonide has protective and deleterious effects in experimental colitis in mice. Biochem Pharmacol 116:73–88. https://doi.org/10.1016/j.bcp.2016.07.010

    Article  PubMed  CAS  Google Scholar 

  21. Fischer A, Gluth M, Weege F, Pape UF, Wiedenmann B, Baumgart DC, Theuring F (2014) Glucocorticoids regulate barrier function and claudin expression in intestinal epithelial cells via MKP-1. Am J Physiol Gastrointest Liver Physiol 306(3):G218–G228. https://doi.org/10.1152/ajpgi.00095.2013

    Article  PubMed  CAS  Google Scholar 

  22. Van Sebille YZA, Gibson RJ, Wardill HR, Secombe KR, Ball IA, Keefe DMK, Finnie JW, Bowen JM (2017) Dacomitinib-induced diarrhoea is associated with altered gastrointestinal permeability and disruption in ileal histology in rats. Int J Cancer J I du Cancer 140(12):2820–2829. https://doi.org/10.1002/ijc.30699

    Article  CAS  Google Scholar 

  23. Gibson RJ, Bowen JM, Cummins AG, Keefe DM (2005) Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat. Clin Exp Med 4(4):188–195. https://doi.org/10.1007/s10238-004-0055-y

    Article  PubMed  CAS  Google Scholar 

  24. Dawson PA, Lan T, Rao A (2009) Bile acid transporters. J Lipid Res 50(12):2340–2357. https://doi.org/10.1194/jlr.R900012-JLR200

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Krag E, Krag B (1976) Regional ileitis (Crohn’s disease). I. Kinetics of bile acid absorption in the perfused ileum. Scand J Gastroenterol 11(5):481–486

    PubMed  CAS  Google Scholar 

  26. Stelzner M, Somasundaram S, Khakberdiev T (2001) Systemic effects of acute terminal ileitis on uninflamed gut aggravate bile acid malabsorption. J Surg Res 99(2):359–364. https://doi.org/10.1006/jsre.2001.6137

    Article  PubMed  CAS  Google Scholar 

  27. Jung D, Fantin AC, Scheurer U, Fried M, Kullak-Ublick GA (2004) Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor. Gut 53(1):78–84

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Bowen JM (2013) Mechanisms of TKI-induced diarrhea in cancer patients. Curr Opin Support Palliat Care 7(2):162–167. https://doi.org/10.1097/SPC.0b013e32835ec861

    Article  PubMed  Google Scholar 

  29. Abbas R, Hug BA, Leister C, Sonnichsen D (2012) A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor. Cancer Chemother Pharmacol 70(1):191–199. https://doi.org/10.1007/s00280-012-1857-3

    Article  PubMed  CAS  Google Scholar 

  30. Barkas F, Liberopoulos E, Kei A, Elisaf M (2013) Electrolyte and acid-base disorders in inflammatory bowel disease. Ann Gastroenterol 26(1):23–28

    PubMed  PubMed Central  Google Scholar 

  31. Priyamvada S, Gomes R, Gill RK, Saksena S, Alrefai WA, Dudeja PK (2015) Mechanisms underlying dysregulation of electrolyte absorption in inflammatory bowel disease-associated diarrhea. Inflamm Bowel Dis 21(12):2926–2935. https://doi.org/10.1097/mib.0000000000000504

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gordon PV, Price WA, Stiles AD, Rutledge JC (2001) Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants. Pediatr Dev Pathol 4(6):532–537

    Article  PubMed  CAS  Google Scholar 

  33. Cyr MM, Baatjes AJ, Dorman SC, Crawford L, Sehmi R, Foley R, Alam R, Byrne PO, Denburg JA (2008) In vitro effects of budesonide on eosinophil-basophil lineage commitment. Open Respir Med J 2:60–66. https://doi.org/10.2174/1874306400802010060

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. West GA, Matsuura T, Levine AD, Klein JS, Fiocchi C (1996) Interleukin 4 in inflammatory bowel disease and mucosal immune reactivity. Gastroenterology 110(6):1683–1695

    Article  PubMed  CAS  Google Scholar 

  35. Kole A, Maloy KJ (2014) Control of intestinal inflammation by interleukin-10. Curr Top Microbiol Immunol 380:19–38. https://doi.org/10.1007/978-3-662-43492-5_2

    PubMed  CAS  Article  Google Scholar 

  36. Beaurepaire C, Smyth D, McKay DM (2009) Interferon-gamma regulation of intestinal epithelial permeability. J Interferon Cytokine Res 29(3):133–144. https://doi.org/10.1089/jir.2008.0057

    Article  PubMed  CAS  Google Scholar 

  37. Nava P, Koch S, Laukoetter MG, Lee WY, Kolegraff K, Capaldo CT, Beeman N, Addis C, Gerner-Smidt K, Neumaier I, Skerra A, Li L, Parkos CA, Nusrat A (2010) Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity 32(3):392–402. https://doi.org/10.1016/j.immuni.2010.03.001

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

This research was funded by Puma Biotechnology. Dr Janet Coller, Discipline of Pharmacology, University of Adelaide assisted with interpretation of mass spectrometry data. Dr Hannah Wardill, Discipline of Physiology, University of Adelaide, and Dr Ysabella Van Sebille, Division of Health Sciences, University of South Australia assisted with the animal study.

Funding

This study was funded by Puma Biotechnology Inc.

Author information

Authors and Affiliations

  1. Adelaide Medical School, University of Adelaide, Level 2 Helen Mayo Building South, Frome Rd, Adelaide, South Australia, 5005, Australia

    Kate R. Secombe, Imogen A. Ball, Joseph Shirren, Anthony D. Wignall, Dorothy Keefe & Joanne M. Bowen

  2. SA Pathology, Adelaide, South Australia, Australia

    John Finnie

  3. Puma Biotechnology Inc, Los Angeles, CA, USA

    Francesca Avogadri-Connors, Elizabeth Olek, David Martin & Susan Moran

Authors
  1. Kate R. Secombe
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  2. Imogen A. Ball
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  11. Joanne M. Bowen
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Corresponding author

Correspondence to Kate R. Secombe.

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Conflict of interest

Kate Secombe, Imogen Ball, Joseph Shirren, Anthony Wignall and John Finnie declare that they have no conflicts of interest. Joanne Bowen has received research funding from Puma Biotechnology, AstraZeneca, Helsinn and Pfizer. Dorothy Keefe is a consultant for and owns stock in Entrinsic Health Solutions. Francesca Avogadri-Connors, Elizabeth Olek, David Martin and Susan Moran were staff of Puma Biotechnology at the time of the study.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.

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Secombe, K.R., Ball, I.A., Shirren, J. et al. Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model. Cancer Chemother Pharmacol 83, 531–543 (2019). https://doi.org/10.1007/s00280-018-3756-8

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  • DOI: https://doi.org/10.1007/s00280-018-3756-8

Keywords

  • Targeted therapies
  • Diarrhea
  • Breast cancer
  • Rat model
  • Neratinib