APR-246 (PRIMA-1 MET ) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines

Deben, Christophe; Lardon, Filip; Wouters, An; Beeck, Ken Op de; Bossche, Jolien Van den; Jacobs, Julie; Steen, Nele Van Der; Peeters, Marc; Rolfo, Christian; Deschoolmeester, Vanessa; Pauwels, Patrick

doi:10.1016/j.canlet.2016.03.017

Cited by 57 publications

(49 citation statements)

References 37 publications

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“…APR-246 (aka PRIMA-1), the first drug in clinical trials that directly targets mutant p53 is currently in a Phase 1b/II clinical trial (PiSSARO, ClinicalTrials.gov ID NCT02098343). APR-246 showed strong synergies with cisplatin in p.Y220C-mutated cancer cell lines (Mohell et al 2015), and also with olaparib in p53-mutated non-small-cell lung cancer cell lines (Deben et al 2016). Further compounds such as PK7088 that specifically target the p.Y220C induced crevice are in preclinical development (Joerger and Fersht 2010; Liu et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events

Meißner¹,

Mark²,

Williams

et al. 2017

Cold Spring Harb Mol Case Stud

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A triple-negative breast cancer patient had no hereditary BRCA1, BRCA2, or TP53 risk variants. After exhaustion of standard treatments, she underwent experimental treatments and whole-exome sequencing of tumor, blood, and a metastasis. Well-tolerated experimental bortezomib monotherapy was administered for a progression-free period of 11 mo. After progression, treatments were changed and the exome data were evaluated, expanded with RNA and exome sequencing of a late-stage metastasis. In the final stage, eribulin alone and in combination with anthracyclines were administered. While suffering from grade 3 adverse events, skin metastases progressed. She lived 51 mo after initial diagnosis.Toxicity from anthracyclines and cisplatin may have been due to associated germline variants CBR3 C4Y and V224M and GSTP1 I105V, respectively. Somatic mutations predicted or reported as pathogenic were detected in 38 genes in tumor tissues. All tumor samples harbored the heterozygous TP53 Y220C variant, known to destabilize p53 and down-regulate p53-mediated apoptosis. The success of bortezomib may be explained by the previously reported up-regulation of caspase-mediated apoptosis, which is p53-independent. Phylogenetic analysis of blood, primary tumor, and two metastases inferred an ancestral tumor cell with 12 expressed tumor mutations from which all three tumors may have evolved.Although our first urgent analysis could only include 40 genes, postmortem analysis uncovered the aggressiveness and suggested experimental therapies including 16 actionable targets, partly validated by immunohistochemistry. Exome and transcriptome analyses yielded comprehensive therapy-relevant information and should be considered for patients at first diagnosis.

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Section: Discussionmentioning

confidence: 99%

Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events

Meißner¹,

Mark²,

Williams

et al. 2017

Cold Spring Harb Mol Case Stud

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“…In the present study, it was identified that PARP-1 inhibition significantly increased p53 expression levels in PanC-1 cells. Deben et al (15) reported that PARP inhibition induces apoptosis in non-small cell lung cancer cell lines via the p53 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

et al. 2017

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Abstract. The present study investigated whether poly(ADP-ribose) polymerase (PARP) has an effect on p53-regulated pancreatic cancer. The results of the present study demonstrated that the expression of PARP affects proliferation and apoptosis of pancreatic cancer cells. Olaparib was used to suppress the expression level of PARP-1 in PanC-1 cells. Decreased expression of PARP-1 suppressed cell proliferation and induced apoptosis of PanC-1 cells when compared with controls. Furthermore, decreased expression of PARP-1 resulted in decreased levels of pro-caspase-3 expression, increased caspase-3 activity, suppressed B-cell lymphoma 2 (Bcl-2) protein expression and increased p53 protein expression in PanC-1 cells. Subsequently, ataxia telangiectasia mutated (ATM) activity was inhibited alongside down-expression of PARP-1 resulting in significantly decreased cellular viability of PanC-1 cells, increased p53 protein expression, decreased expression of pro-caspase-3, increased caspase-3 activity and suppressed Bcl-2 protein expression, when compared with PARP-1 suppression alone. Overall, the in vitro data confirmed that down-expression of PARP-1 suppressed cell proliferation and induced apoptosis of pancreatic cancer via ATM-deficient p53 signaling pathway.

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“…Theoretically, at least half of all cancer patients would benefit from strategies targeting p53. Also, the combination of mutp53 reactivators and traditional anticancer drugs may exhibit synergetic effects, as conventional anticancer drugs usually depend on an intact p53 pathway (Deben et al, ; Fransson et al, ), which expands the application of mutp53 reactivators. Encouragingly, some of the mutp53 reactivators are in clinical trials; PRIMA‐1 Met (APR‐246) and COTI‐2 showed positive results (Deneberg et al, ).…”

Section: Discussionmentioning

confidence: 99%

Salvation of the fallen angel: Reactivating mutant p53

Yang

Wang

Chen

et al. 2019

British J Pharmacology

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The transcription factor p53 is known as the guardian of the genome for its powerful anti-tumour capacity. However, mutations of p53 that undermine their protein structure, resulting in loss of tumour suppressor function and gain of oncogenic function, have been implicated in more than half of human cancers. The crucial role of mutant forms of p53 in cancer makes it an attractive therapeutic target. A large number of candidates, including low MW compounds, peptides, and nucleic acids, have been identified or designed to rescue p53 mutants and reactivate their anti-tumour capacity through a variety of mechanisms. In this review, we summarize the progress made in the reactivation of mutant forms of p53, focusing on the pharmacological mechanisms of the reactivators of p53 mutants.

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APR-246 (PRIMA-1 MET ) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines

Cited by 57 publications

References 37 publications

Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events

Metastatic triple-negative breast cancer patient with TP53 tumor mutation experienced 11 months progression-free survival on bortezomib monotherapy without adverse events after ending standard treatments with grade 3 adverse events

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

Salvation of the fallen angel: Reactivating mutant p53

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