Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations

Abstract

Purpose The mechanism of action of CNDAC (2′-C-cyano-2′-deoxy-1-β-d-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors. The purpose of this study is to investigate the potential of CNDAC for the therapy of ovarian cancer (OC). Methods Drug sensitivity was evaluated using a clonogenic survival assay. Drug combination effects were quantified by median effect analysis. Results OC cells lacking function of the key HR genes, BRCA1 or BRCA2, were more sensitive to CNDAC than corresponding HR proficient cells. The sensitization was associated with greater levels of DNA damage in response to CNDAC at clinically achievable concentrations, manifested as chromosomal aberrations. Three classes of CNDAC-based drug combinations were investigated. First, the PARP1 inhibitors, rucaparib and talazoparib, were selectively synergistic with CNDAC in BRCA1/2 deficient OC cells (combination index < 1) at a relatively low concentration range. Second, cisplatin and oxaliplatin had additive combination effects with CNDAC (combination index ~ 1). Finally, paclitaxel and docetaxel achieved additive cell-killing effects with CNDAC at concentration ranges of the taxanes similar for both BRCA1/2 deficient and proficient OC cells. Conclusions This study provides mechanistic rationales for combining CNDAC with PARP inhibitors, platinum compounds and taxanes in ovarian cancer lacking BRCA1/2 function.

Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1

“…2c) to achieve growth inhibition (Additional file 1: Table S1). Altogether, these results confirmed that OC cells with mutated BRCA1 and deficient HR-related genes are more sensitive to PARPi similarly to other studies [36, 37].

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Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma

“…The ATRX mutants also showed selective sensitivity to the toolbox ataxia telangiectasia mutated (ATM) inhibitor KU60019 and to sapacitabine, an inducer of DNA double strand breaks known to be effective in models of HR deficient cancer ( Fig. 3 b, Fig S3 e-g ) [35] . Aside from inhibitors of the DNA damage response, additional compounds identified by the screen with a high degree of preferential sensitivity in the ATRX mutants were the multi-tyrosine kinase inhibitor sunitinib [36] and, in keeping with screen 1, the HSP 90 inhibitor: 17-AAG [33] .…”

“…In addition to PARP inhibitor sensitivity, we also identify preferential sensitivity to sapacitabine in the ATRX mutated isogenic cell lines. Sapacitabine is a nucleoside analogue that induces double stranded DNA breaks, and has also been shown to be effective in other HRR deficient cancers [ 35 , 42 ]. Therefore further evaluation of this agent for ATRX mutant/deleted neuroblastoma and other HRR deficient childhood tumours is also warranted.…”

“…We identify preferential sensitivity to the toolkit ATM inhibitor KU60019 in the ATRX mutants. The clinical ATM inhibitor AZD0156 is currently in phase 1 trials in adults with advanced solid tumours in combination with either olaparib or irinotecan [ [33] , [34] , [35] , 41 ]. There would therefore also be a strong rationale for further pre-clinical testing of these AZD0156 combinations for ATRX mutant neuroblastoma.…”

Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells

“…We selected CNDAC, because, in contrast to SAMHD1 substrates such as cytarabine and decitabine, it has been proposed to be a SAMHD1 inhibitor [Hollenbaugh et al, 2017]. CNDAC is further interesting due to its unique mechanism of action among deoxycytidine analogues, which is characterised by CNDAC triphosphate (CNDAC-TP) incorporation into DNA initially causing single strand breaks and G2 cell cycle arrest [Hanaoka et al, 1999;Azuma et al, 2001;Liu et al, 2005;Liu et al, 2008;Al Abo et al, 2017;Liu et al, 2018;Liu et al, 2019].…”