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ERCC1/XPF is a DNA endonuclease with variable expression in primary tumor specimens, and has been investigated as a predictive biomarker for efficacy of platinum-based chemotherapy in non-small cell lung cancers where up to 30-60% of tumors harbor low to undetectable ERCC1 expression. The failure of an international, randomized Phase III clinical trial utilizing ERCC1 expression to predict response to platinum-based chemotherapy suggests additional mechanisms underlying the basic biology of ERCC1 in the response to platinum-DNA damage remain unknown. In this work, we aimed to characterize a panel of ERCC1 knockout cell lines generated via CRISPR-Cas9 where we identified a synthetic viable phenotype in response to intestrand crosslinks (ICLs) with ERCC1 deficiency. Characterization of these ERCC1 knockout cell lines revealed loss of ERCC1 hypersensitized cells to cisplatin when wildtype (WT) p53 is retained, while there was only modest sensitivity in cell lines that were p53mutant/null. Additionally, when p53 was disrupted by CRISPR-Cas9 (p53*) in ERCC1 knockout/p53WT cells, there was reduced apoptosis and increased viability after platinum treatment. These results were recapitulated in two patient data sets utilizing p53 mutation analysis and ERCC1 expression to assess Overall Survival. We also show that kinetics of ICL-repair differed between ERCC1 knockout/p53WT and ERCC1 knockout/p53* cells. Finally, we provide evidence that cisplatin tolerance in the context of ERCC1 deficiency relies on DNA-PKcs and BRCA1 function as well as timely entry into S phase suggesting that replication dependent mechanisms are likely involved in promoting platinum tolerance. Building upon these observations, we utilized our established lung cancer cell line models of ERCC1 deficiency to find that platinum tolerance with ERCC1 deficiency relies upon ATR signaling.
Novel Insights Into the Use of ERCC1 as a Biomarker for Response to Platinum-based Chemotherapy in Lung Cancer
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