Cell Reports 2021 ... Epigenetic supports collateral lethality


02 juin 2021

Researchers at the Pole of Pharmacology and Therapeutics report how a metabolism-targeting drug can be delivered to cancer cells to force them to adapt and resist this first-line treatment but also become more vulnerable to a second-line anti-metabolic therapy.


The discovery is published in Cell Reports, June 1st.


Although tumor metabolism has become a major source of inspiration to develop new anticancer drugs, the current number of breakthrough discoveries under clinical evaluation is so far limited. One explanation besides the usual pharmacokinetic and pharmacodynamic issues that stop drug candidates during their development is the metabolic plasticity of tumor cells. In particular, when a metabolic pathway is pharmacologically inhibited, accumulation of metabolites upstream the enzymatic blockade or a deficit in intermediates down the route may foster cancer cells to shift their metabolic preferences to survive and/or keep growing.


Instead of being the passive observers of these adaptations and associated drug resistance, O. Feron and his colleagues reasoned that treating cancer cells to drive them toward specific metabolic paths could represent an attractive strategy if combined with a second treatment that efficiently tackles the new tumor bioenergetic preferences.


This idea stems from another concept named metabolic synthetic lethality that describes how oncogenic mutations by reprogramming cancer cell metabolism may actually offer opportunities to develop selective therapies that would target cancer cells without affecting healthy tissues.


Together with O. Feron, Cyril Corbet used the glycolysis inhibitor 3-bromopyruvate (3-BrPA) to explore this paradigm and document that resistance to this compound actually arises from DNA methylation. Epigenetic adaptation to the cytotoxic effects of 3-BrPA actually led to the silencing of monocarboxylate transporter MCT1. This response that prevented further entry of the drug into cancer cells was rapid and long-lasting even in the absence of a continuous exposure to 3-BrPA.


Two talented collaborators, Catherine Vander Linden (PhD student) and Céline Guilbaud further observed that unexpectedly 3-BrPA-resistant cancer cells mostly rely on glycolysis to sustain their growth, with MCT4 as an essential player to support lactate flux. This shift makes cancer cells particularly suited to adapt to hypoxic conditions and resist OXPHOS inhibitors and anti-proliferative chemotherapy. By contrast, blockade of MCT4 activity in 3-BrPA-exposed cancer cells, either by diclofenac (repurposed drug) or genetic knock-out, leads to inhibition of the growth of derived spheroids and tumors in mice. This study supports a new mode of synthethic lethality (named collateral lethality) according to which metabolic adaptation of tumor cells to a first-line therapy makes them more responsive to a second-line treatment.