Excision repair cross-complementation group 1 (ERCC1) is a DNA repair enzyme 
that is frequently defective in non-small cell lung cancer (NSCLC). Although low 
ERCC1 expression correlates with platinum sensitivity, the clinical 
effectiveness of platinum therapy is limited, highlighting the need for 
alternative treatment strategies. To discover new mechanism-based therapeutic 
strategies for ERCC1-defective tumours, we performed high-throughput drug 
screens in an isogenic NSCLC model of ERCC1 deficiency and dissected the 
mechanism underlying ERCC1-selective effects by studying molecular biomarkers of 
tumour cell response. The high-throughput screens identified multiple clinical 
poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors, such as olaparib 
(AZD-2281), niraparib (MK-4827) and BMN 673, as being selective for ERCC1 
deficiency. We observed that ERCC1-deficient cells displayed a significant delay 
in double-strand break repair associated with a profound and prolonged G₂/M 
arrest following PARP1/2 inhibitor treatment. Importantly, we found that ERCC1 
isoform 202, which has recently been shown to mediate platinum sensitivity, also 
modulated PARP1/2 sensitivity. A PARP1/2 inhibitor-synthetic lethal siRNA screen 
revealed that ERCC1 deficiency was epistatic with homologous recombination 
deficiency. However, ERCC1-deficient cells did not display a defect in RAD51 
foci formation, suggesting that ERCC1 might be required to process PARP1/2 
inhibitor-induced DNA lesions before DNA strand invasion. PARP1 silencing 
restored PARP1/2 inhibitor resistance in ERCC1-deficient cells but had no effect 
in ERCC1-proficient cells, supporting the hypothesis that PARP1 might be 
required for the ERCC1 selectivity of PARP1/2 inhibitors. This study suggests 
that PARP1/2 inhibitors as a monotherapy could represent a novel therapeutic 
strategy for NSCLC patients with ERCC1-deficient tumours.