Phase 1 study of the PARP inhibitor E7449 as a single agent in patients with advanced solid tumors or B-cell lymphoma.

Plummer, Ruth; Dua, Divyanshu; Cresti, Nicola; Suder, Aneta; Drew, Yvette; Prathapan, Vasanthi; Stephens, Peter; Thornton, J.; Heras, Begoña de las; Ink, B.; Lee, Lucy; Matijevic, Mark; McGrath, Shannon; Sarker, Debashis

doi:10.1200/jco.2014.32.15_suppl.e19531

Cited by 5 publications

(9 citation statements)

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“…We also detected that loss of PARylation decreased the frequency of mutations in UVB-treated cells as evidenced by decreased number of colonies after ABT-888 treatment suggesting that PARPi initiate apoptosis of cells with a high content of CPDs. Our results are in accordance with the anti-cancer effect of diverse PARP inhibitors and provide experimental evidence for the photosensitizing effect of PARP inhibitors experienced clinically [100,101]. Nevertheless, it is important to know that therapeutic application of PARP inhibitors might be associated with photosensitivity (sunburn) but not with an increased photocarcinogenesis risk.…”

Section: Discussionsupporting

confidence: 85%

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

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Keratinocytes provide the first line of defense of the human body against carcinogenic ultraviolet (UV) radiation. Acute and chronic UVB-mediated cellular responses were widely studied. However, little is known about the role of mitochondrial regulation in UVB-induced DNA damage. Here, we show that poly (ADP-ribose) polymerase 1 (PARP1) and ataxia-telangiectasia-mutated (ATM) kinase, two tumor suppressors, are important regulators in mitochondrial alterations induced by UVB. Our study demonstrates that PARP inhibition by ABT-888 upon UVB treatment exacerbated cyclobutane pyrimidine dimers (CPD) accumulation, cell cycle block and cell death and reduced cell proliferation in premalignant skin keratinocytes. Furthermore, in human keratinocytes UVB enhanced oxidative phosphorylation (OXPHOS) and autophagy which were further induced upon PARP inhibition. Immunoblot analysis showed that these cellular responses to PARP inhibition upon UVB irradiation strongly alter the phosphorylation level of ATM, adenosine monophosphate-activated kinase (AMPK), p53, protein kinase B (AKT), and mammalian target of rapamycin (mTOR) proteins. Furthermore, chemical inhibition of ATM led to significant reduction in AMPK, p53, AKT, and mTOR activation suggesting the central role of ATM in the UVB-mediated mitochondrial changes. Our results suggest a possible link between UVB-induced DNA damage and metabolic adaptations of mitochondria and reveal the OXPHOS-regulating role of autophagy which is dependent on key metabolic and DNA damage regulators downstream of PARP1 and ATM. IntroductionMitochondria regulate their shape, number, distribution, mass, content of mitochondrial DNA (mtDNA), and metabolic capacity in a process called mitochondrial biogenesis, which requires the orchestration of complex transcriptional control of both nuclear and mitochondrial genes [1,2]. The function of mitochondrial biogenesis is to provide quality control of mitochondria by regulating mitochondrial fission, fusion, and mitophagy [3,4] to maximize the energy utilization of mitochondria [5] to meet cellular and environmental demands. Imbalances or perturbations in these processes can lead to mitochondrial dysfunction [3,6].Accumulating evidence suggests that mitochondria also play a central role in skin physiology. Although, involvement of other organ systems predominates in classical mitochondrial disorders, several cutaneous diseases can be linked to mitochondrial dysfunctions [7]. Interestingly, mitochondria lack functional nucleotide excision repair (NER) pathway [8,9] which is responsible for the removal of ultraviolet (UV)-induced DNA lesions including cyclobutane pyrimidine dimers (CPD). Accumulation of these DNA photoproducts in mtDNA leads to mutations and deletions resulting in mitochondrial alterations which have been associated with photoaging [10,11] and are present in melanoma [12], as well as in non-melanoma skin cancers [13,14]. The other types of mitochondrial alterations such as upregulated oxidative phosphorylation (OXPHOS), mitochondrial memb...

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Section: Discussionsupporting

confidence: 85%

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

Hegedűs

Boros

Fidrus

et al. 2019

Cancers

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“…Pharmacodynamic effects on Wnt signaling were observed in the Wnt1 model, and co-administration of E7449 with a MEK inhibitor, resulted in a synergistic antitumor effect, with no significant toxicity. Dual inhibition of TNKS1/2 and PARP1/2 distinguishes E7449 from existing PARP inhibitors and may lead to a distinct spectrum of clinical opportunity; E7449 is currently in early phase clinical development [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…While E7449 closely parallels previously described inhibitors in terms of PARP inhibition and preclinical properties, significant divergence arises with respect to effects on tankyrase activity. E7449 inhibits TNKS1/2 with IC 50 values from 50 to 120 nmol/L, a dose considered clinically relevant [ 30 ]. An IC 50 value of > 3 μmol/L was determined for olaparib for TNKS1 inhibition using the Trevigen assay.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, no gastrointestinal toxicity was observed in preclinical studies with E7449 despite evidence of Wnt-target perturbation. Moreover, E7449 has been generally well tolerated in cancer patients treated to date, with fatigue (a PARP inhibitor class effect) rather than intestinal toxicity identified as the dose-limiting toxicity in a small phase 1 study [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of TNKS1/2 by E7449 is a significant distinction from traditional inhibitors and the resultant modulation of Wnt/β-catenin signaling may broaden the potential therapeutic applications beyond tumors with deficient DNA repair capacity. Evaluation of E7449 in early clinical studies in cancer patients is underway [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling

McGonigle

Chen

et al. 2015

Oncotarget

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Inhibition of Poly(ADP-ribose) Polymerase1 (PARP1) impairs DNA damage repair, and early generation PARP1/2 inhibitors (olaparib, niraparib, etc.) have demonstrated clinical proof of concept for cancer treatment. Here, we describe the development of the novel PARP inhibitor E7449, a potent PARP1/2 inhibitor that also inhibits PARP5a/5b, otherwise known as tankyrase1 and 2 (TNKS1 and 2), important regulators of canonical Wnt/β-catenin signaling. E7449 inhibits PARP enzymatic activity and additionally traps PARP1 onto damaged DNA; a mechanism previously shown to augment cytotoxicity. Cells deficient in DNA repair pathways beyond homologous recombination were sensitive to E7449 treatment. Chemotherapy was potentiated by E7449 and single agent had significant antitumor activity in BRCA-deficient xenografts. Additionally, E7449 inhibited Wnt/β-catenin signaling in colon cancer cell lines, likely through TNKS inhibition. Consistent with this possibility, E7449 stabilized axin and TNKS proteins resulting in β-catenin de-stabilization and significantly altered expression of Wnt target genes. Notably, hair growth mediated by Wnt signaling was inhibited by E7449. A pharmacodynamic effect of E7449 on Wnt target genes was observed in tumors, although E7449 lacked single agent antitumor activity in vivo, a finding typical for selective TNKS inhibitors. E7449 antitumor activity was increased through combination with MEK inhibition. Particularly noteworthy was the lack of toxicity, most significantly the lack of intestinal toxicity reported for other TNKS inhibitors. E7449 represents a novel dual PARP1/2 and TNKS1/2 inhibitor which has the advantage of targeting Wnt/β-catenin signaling addicted tumors. E7449 is currently in early clinical development.

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A Road Map to Personalizing Targeted Cancer Therapies Using Synthetic Lethality

et al. 2019

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Phase 1 study of the PARP inhibitor E7449 as a single agent in patients with advanced solid tumors or B-cell lymphoma.

Cited by 5 publications

References 0 publications

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

PARP1 Inhibition Augments UVB-Mediated Mitochondrial Changes—Implications for UV-Induced DNA Repair and Photocarcinogenesis

E7449: A dual inhibitor of PARP1/2 and tankyrase1/2 inhibits growth of DNA repair deficient tumors and antagonizes Wnt signaling

A Road Map to Personalizing Targeted Cancer Therapies Using Synthetic Lethality

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