A high-throughput screen identifies PARP1/2 inhibitors as a potential therapy for ERCC1-deficient non-small cell lung cancer

Abstract

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.

New therapeutic perspectives in CCDC6 deficient lung cancer cells

“…Recent advances in genomics have identified a number of genetic alterations in NSCLC that could be therapeutically exploited as predictive biomarkers to guide treatment decisions and customize therapy. 2,3 The use of tyrosine kinase inhibitors to target Epidermal Growth Factor Receptor (EGFR), 4 Anaplstic lymphoma kinase (ALK) 5 and RET protooncogene, rearranged during transfection (RET) 6 is effective, but only in small minority of cases (10)(11)(12)(13)(14)(15)(5)(6)(7) and 2% of NSCLC patients, respectively). A vast majority of NSCLCs do not carry the molecular alterations; thus, disease management is an ongoing challenge.…”

“…13 To better manage NSCLC a number of biomarkers involved in DNA repair, such as ERCC1/2, BRCA1/2, are emerging as predictors of the response to conventional chemotherapeutics. 14,15 In previous work, we documented that CCDC6 (coiled-coildomain containing 6) acts as a proapoptotic protein substrate of ATM, to sustain DNA damage checkpoints in response to genotoxic events. 16,17 Moreover, CCDC6 protects genome integrity by modulating the activity of the phosphatase PP4C directed toward the dephosphorylation on S139 of the histone H2AX (gH2AX) in response to DNA damage.…”

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

“…[10][11][12][13] In addition, screening for synthetic lethality has successfully identified targetable cancer-specific vulnerabilities alone and in combination with existing therapies. [14][15][16][17][18][19][20][21] The novel identification of GLI1 as a gene that regulates vorinostat-mediated apoptosis and the demonstration that a small-molecule GLI1 inhibitor functions cooperatively with vorinostat to induce tumor cell death provides a new avenue for combination therapies using vorinostat and other HDACis.…”

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

“…2). ERCC1 deficiency correlates with sensitivity to agents that stall DNA replication forks, such as platinum salts and PARP inhibitors (3)(4)(5). However, drug resistance and/or cumulative toxicities ultimately occur, limiting drug efficacy.…”

“…DNA repair deficiency sensitizes lung cancer cells to NAD + biosynthesis blockade Mehdi Touat, 1,2,3 Tony Sourisseau, 1 Nicolas Dorvault, 1,4 Roman M. Chabanon, 1,4 Marlène Garrido, 1,4 Daphné Morel, 1,4 Dragomir B. Krastev, 5 Ludovic Bigot, 1 Julien Adam, 1,6 Jessica R. Frankum, 5 Sylvère Durand, 7 Clement Pontoizeau, 8,9,10 Sylvie Souquère, 11 Mei-Shiue Kuo, 1 Sylvie Sauvaigo, 12 Faraz Mardakheh, 13 Alain Sarasin, 14 Ken A. Olaussen, 1,15 Luc Friboulet, 1 Frédéric Bouillaud, 16 Gérard Pierron, 11 Alan Ashworth, 17 Anne Lombès, 16 Christopher J. Lord,5 Jean-Charles Soria, 1,2,15 and Sophie Postel-Vinay (8,9).…”