Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity

Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells. [Display omitted] •TKI resistance promotes PARP inhibitor sensitivity of EGFR mutant lung cancer cells•PARP inhibitor sensitivity can be traced back to the initial TKI persister state•PARP inhibitor sensitivity is mediated by NOX-dependent reactive oxygen species•Abrogating PARylation of NOX activator RAC1 phenocopies PARP inhibitor effects Marcar et al. show that epidermal growth factor receptor mutant (EGFRmut) lung cancer cells with acquired resistance to tyrosine kinase inhibitors (TKIs) exhibit PARP-1 dependence for survival. PARP-1 catalytic function is required for PARylation of RAC1, which restricts NOX-mediated production of cytotoxic reactive oxygen species. Findings suggest combining TKI with PARP inhibition in EGFRmut cancers.