Title:Antiangiogenic Resistance and Cancer Metabolism: Opportunities for Synthetic Lethality
VOLUME: 17 ISSUE: 15
Author(s):Simon Lord, Juan M. Funes, Adrian L Harris and Miguel Quintela-Fandino
Affiliation:Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, Madrid 28029, Spain.
Keywords:Antiangiogenics, cancer metabolism, hypoxia, metabolic reprogramming, mitochondrial switch, synthetic lethality.
Abstract:Antiangiogenic resistance is a major problem in cancer therapeutics. Preclinical
research has identified several compensatory proangiogenic pathways that
arise upon vascular endothelial growth factor inhibition, several of which have led to
the development of novel drugs. However, the combination of two or more targeted
agents in the angiogenesis system is hampered by toxicity, as the system is involved
in normal physiology. We propose a different approach for improving the efficacy of
this drug class, which takes advantage of aberrant cancer metabolism. Several features
distinguish cancer metabolism from that of normal cells, including increased glycolysis,
glutaminolysis, and pentose-phosphate shunt, as well as an anaplerotic shift of the
Krebs cycle. In addition, these aberrations are driven by most of the common mutations
that can be targeted by drugs. Antiangiogenics may hamper the ability of cancer to sustain aberrant
metabolism due to their impacts on nutrient and oxygen supplies, and thus they may induce some metabolic
pathways to become essential for tumor survival (induced essentiality or contextual lethality, a
type of synthetic lethality). Thus, some metabolic and signaling pathways that are otherwise nonessential
may induce synthetic lethality when inhibited in combination with antiangiogenics. The key problems,
however, are interpatient and intratumor heterogeneity, as not all patients with the same tumor
type show the same metabolic traits and the same metabolic reprogramming in response to antiangiogenics.
With each cancer there are heterogeneous hypoxic areas. Integrating dynamic tracking of metabolism
may allow us to tailor our choices of companion drugs with antiangiogenics, taking advantage
of window-of-opportunity designs.
