Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Gallyas, Ferenc; Sümegi, Balázs; Szabó, Csaba

doi:10.3390/cancers12030532

Cited by 58 publications

(42 citation statements)

References 146 publications

(181 reference statements)

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“…In turn, a cytoprotective signalosome (p-ATM–NEMO–Akt–mTOR) is formed, which induces the activation of Akt. Akt is a “master regulator” of various cell-survival pathways; its activation produces a cytoprotective phenotype ( 26 ).…”

Section: Parp Activation a Reemerging Pathophysiological Conceptmentioning

confidence: 99%

“…Multiple lines of in vivo experiments have demonstrated that pharmacological PARP inhibitors or PARP1 deficiency can significantly improve the outcomes of various animal models of acute and chronic lung injury, including endotoxin- or sepsis-induced lung injury, pancreatitis-induced lung injury, lung inflammation elicited by various agents (e.g., zymosan, carrageenan or elastase), ventilator-induced lung injury, environmental agent– or drug-induced lung injury, or lung fibrosis and allergy/asthma–associated lung inflammation and dysfunction ( 26 – 84 ). Table 1 focuses on the findings related to the effect of PARP inhibitors in various forms of ALI and lung inflammation.…”

Section: The Therapeutic Efficacy Of Parp Inhibitors In Alimentioning

confidence: 99%

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Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

Szabó

Martins

Liaudet

2020

Am J Respir Cell Mol Biol

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PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)–associated ALI.

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Section: Parp Activation a Reemerging Pathophysiological Conceptmentioning

confidence: 99%

Section: The Therapeutic Efficacy Of Parp Inhibitors In Alimentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

Szabó

Martins

Liaudet

2020

Am J Respir Cell Mol Biol

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“…Interestingly, nicotinamide has a close relationship with poly (ADP-ribose) polymerase (PARP) (81,87) that is also tied to mTOR and Akt (287,288). PARP is a nuclear protein that binds to DNA strand breaks and cleaves NAD + into nicotinamide and ADP-ribose.…”

Section: Nicotinamide and The Downstream Pathways Of Mtormentioning

confidence: 99%

New Insights for nicotinamide Metabolic disease autophagy and mTOR

Maiese

2020

Front Biosci

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Metabolic disorders, such as diabetes mellitus (DM), are increasingly becoming significant risk factors for the health of the global population and consume substantial portions of the gross domestic product of all nations. Although conventional therapies that include early diagnosis, nutritional modification of diet, and pharmacological treatments may limit disease progression, tight serum glucose control cannot prevent the onset of future disease complications. With these concerns, novel strategies for the treatment of metabolic disorders that involve the vitamin nicotinamide, the mechanistic target of rapamycin (mTOR), mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), AMP activated protein kinase (AMPK), and the cellular pathways of autophagy and apoptosis offer exceptional promise to provide new avenues of treatment. Oversight of these pathways can promote cellular energy homeostasis, maintain mitochondrial function, improve glucose utilization, and preserve pancreatic β-cell function. Yet, the interplay among mTOR, AMPK, and autophagy pathways can be complex and affect desired clinical outcomes, necessitating further investigations to provide efficacious treatment strategies for metabolic dysfunction and DM.

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“…For example, preliminary data demonstrated a synergistic effect of capivasertib in combination with olaparib, indicating that inhibitors of the P13K/AKT pathway potentiate a cytostatic effect of poly ADP-ribose polymerase (PARP) inhibitors in a combination therapy. 65 Recently, Lee et al performed a biomarker-based umbrella trial (VIKTORY; targeted agent eValuation In gastric cancer basket KORea) in GC. 35 This study classified patients with metastatic GC based on eight different biomarker groups and, among 10 associated clinical trials, included a treatment arm with capivasertib plus paclitaxel for PIK3CA mutation.…”

Section: Capivasertib (Azd5363)mentioning

confidence: 99%

Molecular target: pan-AKT in gastric cancer

Kang

Chau

2020

ESMO Open

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The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway is involved in multiple cellular processes, including cell survival, proliferation, differentiation, metabolism and cytoskeletal reorganisation. The downstream effectors of this PI3K pathway are also essential for maintaining physiologic homeostasis, commonly dysregulated in most solid tumours. AKT is the key regulator in PI3K/AKT/mTOR signalling, interacting with multiple intracellular molecules. AKT activation subsequently leads to a number of potential downstream effects, and its aberrant activation results in the pathogenesis of cancer. Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes.

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Role of Akt Activation in PARP Inhibitor Resistance in Cancer

Cited by 58 publications

References 146 publications

Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

Poly(ADP-Ribose) Polymerase Inhibition in Acute Lung Injury. A Reemerging Concept

New Insights for nicotinamide Metabolic disease autophagy and mTOR

Molecular target: pan-AKT in gastric cancer

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