The integrated stress response (ISR) is a key pathway that relays stress signals from damaged or dysfunctional mitochondria. Depending on its extent, the mitochondrially activated ISR (mitoISR) restores mitochondrial homeostasis or triggers apoptosis. As shown by our group and others, mitoISR-inducing drugs efficiently overcome therapy resistance in aggressive cancers that overexpress MYC transcription factors. Yet, molecular determinants that underlie the vulnerability of MYC-driven tumors to the inhibition of mitochondrial gene expression machinery remain poorly understood. Building on our data that reveals a previously unrecognized link between mitoISR and degradation of MYC proteins, this project will dissect mitoISR activities genetically and pharmacologically to elucidate their role in regulating the “undruggable” MYC proteins. We will develop novel inducible MYC/MYCN expression models, avoiding mitochondrial off-target effects of previous systems, to provide unique insights into mitoISR/ISR as potential synthetic lethality targets for therapy of MYC-driven tumors.

Sustainable Development Goals

Masaryk University is committed to the UN Sustainable Development Goals, which aim to improve the conditions and quality of life on our planet by 2030.