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Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy

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DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFβ/PD-L1 Targeted Cancer Immunotherapy

Michael Carr et al.

Summary: Peposertib effectively suppresses the repair of radiation-induced DNA double-strand breaks, enhancing cancer cell killing and response to immunotherapy. By promoting micronuclei formation and inflammatory signaling, it offers a novel approach to more efficacious radioimmunotherapy of cancer. Triple combination of radiation, peposertib, and bintrafusp alfa is superior to dual combinations, suggesting a promising strategy for cancer treatment.

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The DNA-PK Inhibitor AZD7648 Sensitizes Patient-Derived Ovarian Cancer Xenografts to Pegylated Liposomal Doxorubicin and Olaparib Preventing Abdominal Metastases

Alessia Anastasia et al.

Summary: The DNA-PK inhibitor AZD7648, when administered in combination with pegylated liposomal doxorubicin (PLD) or the PARP inhibitor olaparib, shows promising efficacy in delaying disease progression and inhibiting tumor growth and metastasis in ovarian cancer. The combination therapy enhances the therapeutic effect of PLD and olaparib, especially in BRCA-deficient patients.

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Structural insights into inhibitor regulation of the DNA repair protein DNA-PKcs

Shikang Liang et al.

Summary: DNA-PKcs plays a crucial role in DNA repair and its inhibitors show potential for cancer treatment. In this study, cryo-EM structures of human DNA-PKcs in complex with inhibitors were obtained, providing insights into the mechanisms and specificities of the inhibitors.

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Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648

Cho R. Hong et al.

Summary: This study evaluated the radiosensitizing effects of the DNA-PK inhibitor AZD7648 on HNSCC cells, tumors, and normal tissues. The results demonstrated that AZD7648 had potent radiosensitizing effects on tumor cells and also significantly enhanced radiosensitivity in stem cells in the small intestine and oral mucosa.

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DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway

Liu Liu et al.

Summary: DNA damage induces DNA-PK-dependent phosphorylation of Sin1, leading to AKT activation and cell survival.

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Pre-clinical activity of the oral DNA-PK inhibitor, peposertib (M3814), combined with radiation in xenograft models of cervical cancer

Sushmita B. Gordhandas et al.

Summary: The study evaluated the efficacy of DNA-PK inhibitor peposertib (M3814) in combination with radiation therapy in a mouse xenograft model of HPV-associated cervical cancer. The results showed that the combination treatment effectively reduced tumor burden and increased the levels of γ-H2AX, a marker of DNA double-strand breaks, in tumor cells.

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Molecular mechanisms involved in DNA repair in human cancers: An overview of PI3k/Akt signaling and PIKKs crosstalk

Forough Alemi et al.

Summary: The cellular genome is frequently damaged by endogenous and exogenous factors, which activate PIKKs family members in DNA damage response. The DDR system protects cells from genotoxicants and repairs DNA damage, while overactivation of the PI3K/Akt pathway can stimulate DDR process leading to increased DNA repair.

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Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer

Mary Smithson et al.

Summary: Treatment of locally advanced rectal cancer involves chemoradiation and surgery, with variable patient response. Identifying mechanisms of resistance is critical for improved outcomes. In this study, we explored the potential of a DNA-PK inhibitor, M3814, to enhance treatment response. Our findings suggest that combining M3814 with standard of care treatment improves response in some rectal cancer models, but other repair mechanisms may limit its effect.

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A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours

Mark T. J. van Bussel et al.

Summary: This phase 1 trial aimed to determine the maximum-tolerated dose and recommended phase 2 dose of peposertib, a DNA-dependent protein kinase inhibitor, in patients with advanced solid tumors. Peposertib was well-tolerated and showed modest efficacy in unselected tumors, with the recommended dose declared as 400 mg twice daily. Further studies are ongoing with peposertib/chemo-radiation combinations.

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Structure of an activated DNA-PK and its implications for NHEJ

Xuemin Chen et al.

Summary: This study reports cryo-EM structures of DNA-PK in both inactive and activated forms bound to DNA end or complexed with Ku70/80 and DNA, revealing the sequential transition of DNA-PK from inactive to activated forms. Activation of the kinase involves unprecedented stretching and twisting within individual solenoid segments, indicating a general regulatory mechanism of HEAT-repeat proteins.

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Activation of homologous recombination in G1 preserves centromeric integrity

Duygu Yilmaz et al.

Summary: Centromeric integrity is crucial for proper chromosome segregation during cell division. DNA breaks at centromeres in G1 recruit homologous recombination machinery, involving specific histone variants, chaperones, and histone modifications. Inhibiting homologous recombination in G1 leads to centromeric instability and chromosomal translocations, highlighting the importance of licensing homologous recombination at centromeric breaks throughout the cell cycle.

NATURE (2021)

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Phosphoinositide 3-Kinase (PI3K) Reactive Oxygen Species (ROS)-Activated Prodrug in Combination with Anthracycline Impairs PI3K Signaling, Increases DNA Damage Response and Reduces Breast Cancer Cell Growth

Rosalin Mishra et al.

Summary: RIDR-PI-103 is a novel prodrug that releases PI-103 in a controlled manner under high ROS conditions to inhibit PI3K. It demonstrates cytotoxicity in breast cancer cells and when combined with doxorubicin, can suppress cancer cell growth and proliferation. Pharmacokinetic studies in mice show promising results for potential therapeutic use in breast cancer treatment.

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A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors

Analia Azaro et al.

Summary: Notch signaling is important in cancer development. Combining crenigacestat with other anticancer agents showed poor tolerability and disappointing clinical activity in patients with advanced or metastatic solid tumors.

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Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma

Marjorie G. Zauderer et al.

Summary: LY3023414 monotherapy at a dose of 200 mg BID showed acceptable safety and manageable side effects, but limited efficacy in patients with advanced mesothelioma. The overall response rate was 2.4%, with a disease control rate of 43%. Common adverse events included fatigue, nausea, decreased appetite, vomiting, and diarrhea.

INVESTIGATIONAL NEW DRUGS (2021)

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Inhibition of DNA-PK with AZD7648 Sensitizes Tumor Cells to Radiotherapy and Induces Type I IFN-Dependent Durable Tumor Control

Kyoko Nakamura et al.

Summary: The combination of AZD7648 with radiotherapy induced complete tumor regressions in a significant proportion of mice, dependent on CD8T cells and modulating an anticancer immune response. Immunological consequences included a reduction in T-cell PD-1 expression, increased NK-cell granzyme B expression, and elevated type I IFN signaling.

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Mol* Viewer: modern web app for 3D visualization and analysis of large biomolecular structures

David Sehnal et al.

Summary: Large biomolecular structures are being determined experimentally using established techniques such as crystallography and electron microscopy, with performance requirements for visualization and analysis tools increasing rapidly. The Mol* Viewer is an advanced online web-native 3D visualization tool that allows visualization of complex structures, and is the primary tool used by PDBe and RCSB PDB.

NUCLEIC ACIDS RESEARCH (2021)

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DNA-PKc inhibition overcomes taxane resistance by promoting taxane-induced DNA damage in prostate cancer cells

Olivia S. Chao et al.

Summary: This study indicates that DDR genes, particularly DNA-PKc, play a crucial role in promoting taxane resistance in mCRPC. Inhibiting DNA-PKc may provide a novel strategy to restore taxane sensitivity in taxane-refractory mCRPC.

PROSTATE (2021)

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DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia

Eric Haines et al.

Summary: Peposertib (M3814) is an effective DNA-PK inhibitor that enhances ATM/p53 signaling, leading to increased p53-dependent anti-tumor activity. In acute leukemia cells, M3814 combined with DNA double-strand break-inducing agents sensitizes p53 wild-type cells through p53-dependent apoptosis, further enhancing daunorubicin-induced myeloid cell differentiation.

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HPV16 E6 enhances the radiosensitivity in HPV-positive human head and neck squamous cell carcinoma by regulating the miR-27a-3p/SMG1 axis

Dan Long et al.

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DNA-Dependent Protein Kinase Catalytic Subunit: The Sensor for DNA Double-Strand Breaks Structurally and Functionally Related to Ataxia Telangiectasia Mutated

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Summary: DNA-dependent protein kinase (DNA-PK) plays a key role in DNA damage repair and maintenance of genomic stability through its catalytic subunit (DNA-PKcs) and Ku70/Ku80 heterodimer. It acts as a sensor for DNA double-stranded breaks (DSB) and is essential for nonhomologous end joining (NHEJ) repair. Dysfunction in DNA-PKcs or Ku functions can lead to detrimental phenotypes, especially in neuronal and immune systems.
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DNA-PK inhibition by M3814 enhances chemosensitivity in non-small cell lung cancer

Manni Wang et al.

Summary: The study identified that the DNA-PK inhibitor M3814 enhanced the anti-tumor effect of chemotherapy in NSCLC cell lines, providing a theoretical basis for its potential use in clinical practice to optimize NSCLC treatment.

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Dual mTOR/DNA-PK Inhibitor CC-115 Induces Cell Death in Melanoma Cells and Has Radiosensitizing Potential

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AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity

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Akt1 Stimulates Homologous Recombination Repair of DNA Double-Strand Breaks in a Rad51-Dependent Manner

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