STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer
Stephanie Totten, Young Kyuen Im, Eduardo Cepeda Cañedo, Ouafa Najyb, Alice Quynh Huong Nguyen, Steven Hébert, Ryuhjin Ahn, Kyle Lewis, Benjamin Lebeau, Rachel La Selva, Valérie Sabourin, Constanza Martínez, Paul Savage, Hellen Kuasne, Daina Avizonis, Nancy Santos Martínez, Catherine Chabot, Adriana Aguilar‐Mahecha, Marie-Line Goulet, Matthew Dankner, Michael Witcher, Kevin Petrecca, Mark Basik, Michaël Pollak, Ivan Topisirović, Rongtuan Lin, Peter M. Siegel, Claudia L. Kleinman, Morag Park, Julie St‐Pierre, Josie Ursini‐Siegel
Abstract
Bioenergetic perturbations driving neoplastic growth increase the production of reactive oxygen species (ROS), requiring a compensatory increase in ROS scavengers to limit oxidative stress. Intervention strategies that simultaneously induce energetic and oxidative stress therefore have therapeutic potential. Phenformin is a mitochondrial complex I inhibitor that induces bioenergetic stress. We now demonstrate that inflammatory mediators, including IFNγ and polyIC, potentiate the cytotoxicity of phenformin by inducing a parallel increase in oxidative stress through STAT1-dependent mechanisms. Indeed, STAT1 signaling downregulates NQO1, a key ROS scavenger, in many breast cancer models. Moreover, genetic ablation or pharmacological inhibition of NQO1 using β-lapachone (an NQO1 bioactivatable drug) increases oxidative stress to selectively sensitize breast cancer models, including patient derived xenografts of HER2+ and triple negative disease, to the tumoricidal effects of phenformin. We provide evidence that therapies targeting ROS scavengers increase the anti-neoplastic efficacy of mitochondrial complex I inhibitors in breast cancer.