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Reconciling environment-mediated metabolic heterogeneity with the oncogene-driven cancer paradigm in precision

Catherine Vander Linden1, Cyril Corbet1

  • 1Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, 57 Avenue Hippocrate, B1.57.04, B-1200 Brussels, Belgium.

Seminars in Cell & Developmental Biology
|May 20, 2019
PubMed

Insights

Precision oncology faces challenges from drug resistance. The tumor microenvironment (TME) drives resistance through metabolic changes, like lactate symbiosis and oxidative phosphorylation (OXPHOS), impacting treatment outcomes.

Area of Science:

  • Oncology
  • Cancer Biology
  • Metabolic Research

Background:

  • Precision oncology aims to tailor treatments to individual genetic profiles for optimal response.
  • Drug resistance and tumor relapse remain significant challenges, limiting the efficacy of targeted therapies.
  • The tumor microenvironment (TME) significantly influences tumor heterogeneity and treatment outcomes, beyond genetic factors.

Purpose of the Study:

  • To review the role of TME-mediated metabolic heterogeneities in therapeutic failure.
  • To elucidate how metabolic symbiosis and oxidative phosphorylation (OXPHOS) contribute to adaptive resistance.
  • To discuss metabolism-interfering strategies for eradicating therapy-resistant cancer cells.

Main Methods:

  • Literature review focusing on TME-mediated metabolic adaptations in cancer.
  • Analysis of mechanisms of adaptive resistance, including lactate symbiosis and OXPHOS.
  • Exploration of preclinical models for TME-driven metabolic heterogeneity.

Main Results:

  • TME-driven metabolic heterogeneities actively contribute to treatment failure in precision oncology.
  • Lactate-based metabolic symbiosis serves as an adaptive resistance mechanism against targeted therapies.
  • Oxidative phosphorylation (OXPHOS) supports the survival and growth of therapy-resistant tumor cells across various cancers.

Conclusions:

  • Targeting TME-mediated metabolic pathways, particularly OXPHOS, offers a promising strategy to overcome drug resistance.
  • Integrating TME-driven metabolic heterogeneity into precision oncology frameworks is crucial for improving patient outcomes.
  • Further research and development of metabolism-interfering therapies are needed to combat relapse-sustaining cancer cells.
Keywords:
CancerDrug resistanceMetabolismOrganoidOxidative phosphorylationPrecision oncologyTargeted therapy

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