Overexpression of MYC is widespread in human cancer, often as a consequence of mutation in upstream mitogenic pathways such as EGFR-RAS and WNT-βCatenin. De-regulated MYC perturbs many aspects of cell function but its influence on cellular metabolism may impart specific vulnerabilities that can be exploited for cancer therapy [1]. Two new studies shine the spotlight on oxidative stress as a specific vulnerability in MYC-dependent cancers and pinpoint NUAK1 and AMPK as key participants in how cancer cells cope with oxidative stress [2, 3].

Relating the genetic model to human disease, multiple human CRC cell lines were exquisitely sensitive to pharmacological inhibition of NUAK1 and again were rescued by provision of exogenous anti-oxidants. Tellingly, the human CRC cell lines were also rescued by depletion of cMYC, whereas forced expression of MYC in drug-resistant cells conferred sensitivity to the NUAK1 inhibitor, firmly supporting our previous demonstration of a synthetic lethal requirement for NUAK1 in MYC-de-regulated cells [4].

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