Molecular correlates of sensitivity to PARP inhibition beyond homologous recombination deficiency in pre-clinical models of colorectal cancer point to wild-type TP53 activity

Abstract

Background PARP inhibitors are active in various tumour types beyond BRCA -mutant cancers, but their activity and molecular correlates in colorectal cancer (CRC) are not well studied. Methods Mutations and genome-wide mutational patterns associated with homologous recombination deficiency (HRD) were investigated in 255 primary CRCs with whole-exome sequencing and/or DNA copy number data. Efficacy of five PARP inhibitors and their molecular correlates were evaluated in 93 CRC cell lines partly annotated with mutational-, DNA copy number-, and/or gene expression profiles. Post-treatment gene expression profiling and specific protein expression analyses were performed in two pairs of PARP inhibitor sensitive and resistant cell lines. Findings A subset of microsatellite stable (MSS) CRCs had truncating mutations in homologous recombination-related genes, but these were not associated with genomic signatures of HRD. Eight CRC cell lines (9%) were sensitive to PARP inhibition, but sensitivity was not predicted by HRD-related genomic and transcriptomic signatures. In contrast, drug sensitivity in MSS cell lines was strongly associated with TP53 wild-type status (odds ratio 15.7, p = 0.023) and TP53-related expression signatures. Increased downstream TP53 activity was among the primary response mechanisms, and TP53 inhibition antagonized the effect of PARP inhibitors. Wild-type TP53-mediated suppression of RAD51 was identified as a possible mechanism of action for sensitivity to PARP inhibition. Interpretation PARP inhibitors are active in a subset of CRC cell lines and preserved TP53 function may increase the likelihood of response.

Responsive signatures established by pharmaco-transcriptomic correlation analysis identifies subsets for PARP-targeted therapy and reveals potential synergistic interactors

“…The results suggest that the PARPi signatures might be independent of the HRD signature. In line with this, recent studies support the expansion of PARP-targeted therapy in cancer irrespective of classical HRD signatures [5][6][7]. Next, we applied PARPis sensitivity and resistance gene signatures to both cancer cell lines and patient samples to identify cancer subtypes that are potentially vulnerable to PARPi.…”

“…McGrail et al [23] used gene expression profiles from ovarian and breast cancer cell lines that display high sensitivity to olaparib and rucaparib, leading to deriving a transcriptional algorithm that can improve the prediction sensitivity to PARP inhibitors. In line with this, recent studies support the expansion of PARP-targeted therapy in cancer irrespective of classical HRD signatures [5][6][7]. In a recent phase III clinical trial recruiting patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, the therapeutic benefits from PARPi niraparib is regardless of the presence or absence of HRD [5].…”

“…Beyond SSB repair, increasing evidence has also suggested that PARP is implicated in numerous other biological processes, such as oxidative stress response and mitochondrial homeostasis [3,4]. As such, recently there has been increasing evidence supporting the expansion of PARP-targeted therapy beyond HRD [5][6][7]. However, biomarkers predicting sensitivity/resistance to PARP inhibitors (PARPis) and cancer subsets vulnerable to PARP targeted therapies remain to be defined [8].…”

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines

“…Thus, metformin inhibits cancer cell growth and survival in both p53-dependent and p53-independent ways. Smeby et al showed that talazoparib, another PARPi, increases the number of TP53-positive nuclei in p53 WT cells, suggesting that the response to PARPis may provide a link between wild-type TP53 and HR deficiency, connected with RAD51 [ 67 ]. However, long-term (five days) treatment with 5 μM olaparib downregulates p53 in the p53 MUT ovarian cancer cell line OVCAR-3, whereas in the p53 WT cell line A2780, it upregulates p53 expression [ 68 ].…”

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

“…In this respect, in vitro studies have shown a synergistic effect of Olaparib and 5-FU in MSI-H CRC [272], whereas Olaparib monotherapy showed benefits in MSS CRC with non-functional HR, and was proposed as maintenance therapy in patients responsive to oxaliplatin-based regimens [273]. The enrichment of PARPi sensitive MSS cell lines was observed in those with preserved TP53 function and TP53-mediated suppression of RAD51 was appointed as a possible mechanism of action [274]. Further, data from 99 MSS CRC cell lines revealed that functionality of HR repair determined in the RAD51 assay could discriminate for PARPi susceptible CRC tumors, in which no increase in the percentage of RAD51 foci positive nuclei was observed upon radiation [273].…”