DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade

Touat, Mehdi; Sourisseau, Tony; Dorvault, Nicolas; Chabanon, R; Garrido, M del R; Morel, Daphné; Krastev, Dragomir B.; Bigot, Ludovic; Adam, Julien; Frankum, Jessica; Durand, Sylvère; Pontoizeau, Clément; Souquère, Sylvie; Kuo, Mei-Shiue; Sauvaigo, Sylvie; Mardakheh, Faraz K.; Sarasin, Alain; Olaussen, Ken A.; Friboulet, Luc; Bouillaud, Frédéric; Pierron, Gérard; Ashworth, Alan; Lombès, Anne; Lord, Christopher J.; Soria, Jean‐Charles; Postel-Vinay, Sophie

doi:10.1172/jci90277

Cited by 19 publications

(17 citation statements)

References 46 publications

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“…We hypothesized that lack of function of a key DNA repair tumor suppressor gene, such as ERCC1, in tumor cells, might influence the molecular processes that control antitumor cell immune responses. To address this hypothesis in a relatively unbiased fashion, we first used RNA-Seq to profile the transcriptome of isogenic ERCC1-defective and WT A549 NSCLC cells (31,32). Briefly, this isogenic model was generated using zinc finger targeting of ERCC1, and consists of one A549-ERCC1 WT/WT parental cell line; one ERCC1-heterozygous cell line (herein referred to as A549-ERCC1 +/-); and 3 ERCC1 -/clones, in which we reconfirmed no detectable levels of ERCC1 ( Figure 1, A and B) and which are characterized by exquisite sensitivity to cisplatin (31) -highlighting their clinical relevance (26) -and to PARPi (28) (Supplemental Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

“…In order to evaluate whether this enhanced cell-autonomous immune signaling could shape the tumor microenvironment, we estimated the extent of tumor-infiltrating lymphocytes (TILs) in a series of 55 human tumor samples derived from patients with resected lung adenocarcinoma (stages I, II, and IIIA). ERCC1 status in these tumors was evaluated by IHC as previously described (32), and TILs were assessed using a morphology-based coverage score. This analysis identified a statistically significant association between low ERCC1 expression and high levels of TILs (P = 0.0265, Mann-Whitney U test, Figure 2, B and C).…”

Section: Resultsmentioning

confidence: 99%

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PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

Chabanon

Muirhead

Krastev

et al. 2019

Journal of Clinical Investigation

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225

149

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The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

Chabanon

Muirhead

Krastev

et al. 2019

Journal of Clinical Investigation

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225

149

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“…The advent of immune checkpoint inhibitors has transformed the management of several tumour types. There is a preclinical rational suggesting that PARP inhibition may trigger neoantigen and non-neoantigen-based mechanisms of tumour cell recognition by the immune system, making PARPi a potential partner for combination with immune checkpoint inhibitors [92][93][94]. A range of clinical trials exploring these combinations are now underway and may provide evidence of this clinical effect [95].…”

Section: Closing Remarks and Future Directionsmentioning

confidence: 99%

A decade of clinical development of PARP inhibitors in perspective

Mateo

Lord

Serra³

et al. 2019

Annals of Oncology

456

380

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Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/ BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.

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“…Other cancer types with DNA repair deficiencies have been identified as selectively sensitive to NAMPT inhibitors. Nonsmall cell lung cancers (NSCLC) with excision repair crosscomplementation group 1 (ERCC1) deficiency were exquisitely sensitive to NAMPT inhibitors, in vitro and in vivo (98). ERCC1 deficiency is also associated with mitochondrial defects, suggesting that additional factors may contribute to NAMPT inhibitor sensitivity in this cancer subtype.…”

Section: Dna Damage Repair Responsementioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade

Cited by 19 publications

References 46 publications

PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

PARP inhibition enhances tumor cell–intrinsic immunity in ERCC1-deficient non–small cell lung cancer

A decade of clinical development of PARP inhibitors in perspective

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

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