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

BioRxiv : the Preprint Server for Biology
Arran HodgkinsonOvidiu Radulescu


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 ...Continue Reading

Related Concepts

Drug Resistance
Biological Evolution
Mitogen-Activated Protein Kinase Kinases
Anatomical Space Structure

Related Feeds

Cancer Genomics (Preprints)

Cancer genomics employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest preprints here.

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Cellular Immunometabolism

Immunometabolism involves not only the way metabolites are digested by the immune system, but the way in which they can alter the pathway of the immune system. These responses occur in day-to-day healthy cell functioning, but can result in diseases, such as autoimmune disorders. Discover the latest research on cellular immunometabolism here.

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.