NAMPT inhibition is a novel synthetic lethal therapeutic approach exploiting nuclear-mitochondrial crosstalk in ERCC1-deficient populations.

Abstract

e23159 Background: ERCC1 (Excision Repair Cross-Complementation group 1) deficiency is the most frequent DNA repair defect in non-small cell lung cancers (NSCLC), making this enzyme an attractive therapeutic target for synthetic lethal (SL) approaches. Previous data support that DNA damage response is involved in regulation of metabolic homeostasis. We hypothesized that ERCC1 deficiency resulted in metabolic reprogramming of cancer cells that in turn generated specific vulnerabilities. Methods: High-throughput proteomic SILAC (stable isotope labeling by aminoacids in cell culture) and metabolomic (LC-MS, GC-MS, LC-QTOF) profiling were performed on a in-house generated NSCLC model of ERCC1 deficiency. Nicotinamide phosphoribosyltransferase (NAMPT) was selected as main hit and revalidated in low-throughput. Sensitivity to NAMPT inhibition was assessed in several NSCLC models. Potential SL interactions were investigated using functional DNA repair and metabolic assays, and transmission electronic microscopy (TEM). Results: We found marked metabolic rewiring in ERCC1-deficient populations, including decreased NAMPT and NAD+ levels and defects in the tricarboxylic acid cycle. These caused exquisite selective sensitivity to NAMPT inhibition in several in vitro and in vivoNSCLC models; these effects were reversed by the restoration of a functional ERCC1 isoform, establishing a causal link with the ERCC1 defective state. TEM, functional DNA repair and metabolic studies revealed structural and functional defects in the mitochondria of ERCC1-deficient cells, and allowed us to propose a model for this nuclear-mitochondrial SL link. A correlation between NAMPT expression and ERCC1 expression was observed in NSCLC patient samples. Conclusions: These findings open novel therapeutic opportunities that exploit a previously undescribed nuclear/mitochondrial SL link between ERCC1 deficiency and NAMPT inhibition in NSCLC. This highlights the potential for targeting DNA repair / metabolic crosstalk for cancer therapy, and support the evaluation of NAMPT inhibitors in ERCC1-deficient tumors.