Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Spatio-Genetic and Phenotypic Modelling Elucidates Resistance and Re-Sensitisation to Treatment in Heterogeneous Melanoma

Arran Hodgkinson, Laurent Le Cam, Dumitru Trucu, Ovidiu Radulescu
doi: https://doi.org/10.1101/463877
Arran Hodgkinson
aDynamique des Interaction Membranaires Normales et Pathologique, Université de Montpellier, Montpellier, France
bInstitut de Recherche en Cancérologie de Montpellier, Montpellier, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laurent Le Cam
bInstitut de Recherche en Cancérologie de Montpellier, Montpellier, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dumitru Trucu
cDivision of Mathematics, University of Dundee, Dundee, Scotland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ovidiu Radulescu
aDynamique des Interaction Membranaires Normales et Pathologique, Université de Montpellier, Montpellier, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Although novel targeted therapies have significantly improved the overall survival of patients with advanced melanoma, understanding and combatting drug resistance remains a major clinical challenge. Using partial differential equations, we describe the evolution of a cellular population through time, space, and phenotype dimensions, in the presence of various drug species. We then use this framework to explore models in which resistance is attained by either mutations (irreversible) or plasticity (reversible). Numerical results suggest that punctuated evolutionary assumptions are more consistent with results obtained from murine melanoma models than gradual evolution. Furthermore, in the context of an evolving tumour cell population, sequencing the treatment, for instance applying immunotherapy before BRAF inhibitors, can increase treatment effectiveness. However, drug strategies which showed success within a spatially homogeneous tumour environment were unsuccessful under heterogeneous conditions, suggesting that spatio-environmental heterogeneity may be the greatest challenge to tumour therapies. Plastic metabolic models are additionally capable of reproducing the characteristic resistant tumour volume curves and predicting re-sensitisation to secondary waves of treatment observed in patient derived xenograft (PDX) melanomas treated with MEK and BRAF inhibitors. Nevertheless, secondary relapse due to a pre-adapted subpopulation, remaining after the first wave of treatment, results in a more rapid development of resistance. Our model provides a framework through which tumour resistance can be understood and would suggest that carefully phased treatments may be able to overcome the development of long-term resistance in melanoma.

Footnotes

  • Email addresses: arran.hodgkinson{at}umontpellier.fr (Arran Hodgkinson), laurent.lecam{at}inserm.fr (Laurent Le Cam), trucu{at}maths.dundee.ac.uk (Dumitru Trucu), ovidiu.radulescu{at}umontpellier.fr (Ovidiu Radulescu)

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Back to top
PreviousNext
Posted November 07, 2018.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Spatio-Genetic and Phenotypic Modelling Elucidates Resistance and Re-Sensitisation to Treatment in Heterogeneous Melanoma
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Spatio-Genetic and Phenotypic Modelling Elucidates Resistance and Re-Sensitisation to Treatment in Heterogeneous Melanoma
Arran Hodgkinson, Laurent Le Cam, Dumitru Trucu, Ovidiu Radulescu
bioRxiv 463877; doi: https://doi.org/10.1101/463877
Reddit logo Twitter logo Facebook logo LinkedIn logo Mendeley logo
Citation Tools
Spatio-Genetic and Phenotypic Modelling Elucidates Resistance and Re-Sensitisation to Treatment in Heterogeneous Melanoma
Arran Hodgkinson, Laurent Le Cam, Dumitru Trucu, Ovidiu Radulescu
bioRxiv 463877; doi: https://doi.org/10.1101/463877

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Cancer Biology
Subject Areas
All Articles
  • Animal Behavior and Cognition (4663)
  • Biochemistry (10320)
  • Bioengineering (7647)
  • Bioinformatics (26266)
  • Biophysics (13486)
  • Cancer Biology (10655)
  • Cell Biology (15372)
  • Clinical Trials (138)
  • Developmental Biology (8473)
  • Ecology (12787)
  • Epidemiology (2067)
  • Evolutionary Biology (16806)
  • Genetics (11374)
  • Genomics (15438)
  • Immunology (10586)
  • Microbiology (25099)
  • Molecular Biology (10176)
  • Neuroscience (54271)
  • Paleontology (399)
  • Pathology (1663)
  • Pharmacology and Toxicology (2884)
  • Physiology (4329)
  • Plant Biology (9216)
  • Scientific Communication and Education (1583)
  • Synthetic Biology (2547)
  • Systems Biology (6765)
  • Zoology (1459)