Synthetic lethality as an engine for cancer drug target discovery

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 19(1), P. 23 - 38

Published: Nov. 11, 2019

Language: Английский

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Replication gaps are a key determinant of PARP inhibitor synthetic lethality with BRCA deficiency

Molecular Cell, Journal Year: 2021, Volume and Issue: 81(15), P. 3128 - 3144.e7

Published: July 2, 2021

Language: Английский

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Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: June 17, 2021

To identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function Polθ, including ART558. ART558 inhibits major Polθ-mediated process, Theta-Mediated End Joining, without targeting Non-Homologous Joining. In addition, elicits damage and synthetic lethality BRCA1- or BRCA2-mutant tumour cells enhances effects a PARP inhibitor. Genetic perturbation screening revealed that defects 53BP1/Shieldin complex, which cause inhibitor resistance, result vitro vivo sensitivity small molecule Polθ inhibitors. Mechanistically, increases biomarkers single-stranded 53BP1-defective whilst inhibition nucleases promote end-resection reversed these effects, implicating lethal mechanism-of-action. Taken together, observations describe drug class BRCA-gene synergy, as well biomarker-defined mechanism PARPi-resistance.

Language: Английский

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Harnessing DNA Double-Strand Break Repair for Cancer Treatment

Frontiers in Oncology, Journal Year: 2019, Volume and Issue: 9

Published: Dec. 10, 2019

DNA double-strand breaks (DSBs) are highly deleterious, with a single unrepaired DSB being sufficient to trigger cell death. Compared healthy cells, cancer cells have higher burden due oncogene-induced replication stress and acquired defects in damage response (DDR) mechanisms. Consequently, hyperproliferating rely on efficient repair for their survival. Moreover, augmented capacity is major cause of radio- chemoresistance and, ultimately, recurrence. Although inherited DDR can predispose individuals develop certain cancers, the very same vulnerability may be therapeutically exploited preferentially kill tumor cells. A paradigm targeted therapy has emerged cancers that exhibit mutations BRCA1 or BRCA2 suppressor genes, conferring strong defect homologous recombination, error-free pathway. Clinical validation such approaches, commonly described as synthetic lethality (SL), been provided by regulatory approval poly(ADP-ribose) polymerase 1 inhibitors (PARPi) monotherapy BRCA1/2-mutated breast ovarian tumors. In this review, we will describe different mechanisms discuss how specific features could therapy. emphasis put advances combinatorial treatment modalities SL approaches arising from pathway interdependencies.

Language: Английский

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Mechanism, cellular functions and cancer roles of polymerase-theta-mediated DNA end joining

Nature Reviews Molecular Cell Biology, Journal Year: 2021, Volume and Issue: 23(2), P. 125 - 140

Published: Sept. 14, 2021

Language: Английский

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Replication Gaps Underlie BRCA Deficiency and Therapy Response

Cancer Research, Journal Year: 2020, Volume and Issue: 81(5), P. 1388 - 1397

Published: Nov. 12, 2020

Defects in DNA repair and the protection of stalled replication forks are thought to underlie chemosensitivity tumors deficient hereditary breast cancer genes

Language: Английский

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Synthetic Lethality in Cancer Therapeutics: The Next Generation

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(7), P. 1626 - 1635

Published: April 1, 2021

Abstract Synthetic lethality (SL) provides a conceptual framework for tackling targets that are not classically “druggable,” including loss-of-function mutations in tumor suppressor genes required carcinogenesis. Recent technological advances have led to an inflection point our understanding of genetic interaction networks and ability identify wide array novel SL drug targets. Here, we review concepts lessons emerging from first-generation trials aimed at testing drugs, discuss how the nature targeted lesion can influence therapeutic outcomes, highlight need develop clinical biomarkers distinct those based on paradigms developed target activated oncogenes. Significance: offers approach targeting loss function DNA repair genes, as well amplification and/or overexpression cannot be directly. A next generation tumor-specific alterations targetable through has emerged high-throughput CRISPR technology, heralding only new opportunities development, but also important challenges development optimal predictive biomarkers.

Language: Английский

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DNA repair defects in cancer and therapeutic opportunities

Genes & Development, Journal Year: 2022, Volume and Issue: 36(5-6), P. 278 - 293

Published: March 1, 2022

DNA repair and damage signaling pathways are critical for the maintenance of genomic stability. Defects contribute to tumorigenesis, but also render cancer cells vulnerable reliant on remaining activities. Here, we review major classes defects in cancer, instability that they give rise to, therapeutic strategies exploit resulting vulnerabilities. Furthermore, discuss impacts both targeted therapy immunotherapy, highlight emerging principles targeting therapy.

Language: Английский

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POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(24), P. 4664 - 4680.e9

Published: Nov. 30, 2022

POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and overexpressed in many cancers. inhibitors confer synthetic lethality HR Shieldin-deficient cancer cells, which has been proposed to reflect critical dependence on the pathway MMEJ. Whether also operates independent MMEJ remains unexplored. Here, we show that POLQ-deficient cells accumulate post-replicative ssDNA gaps upon BRCA1/2 loss or PARP inhibitor treatment. Biochemically, cooperation between helicase polymerase activities promotes RPA displacement ssDNA-gap fill-in, respectively. capable gap skipping (MMGS), generates deletions during resemble genomic scars prevalent overexpressing Our findings implicate mutagenic sealing, could drive genome evolution whose places dependency for protection cellular viability.

Language: Английский

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Biomimetic Macrophage Membrane-Camouflaged Nanoparticles Induce Ferroptosis by Promoting Mitochondrial Damage in Glioblastoma

ACS Nano, Journal Year: 2023, Volume and Issue: 17(23), P. 23746 - 23760

Published: Nov. 22, 2023

The increasing understanding of ferroptosis has indicated its role and therapeutic potential in cancer; however, this knowledge yet to be translated into effective therapies. Glioblastoma (GBM) patients face a bleak prognosis encounter challenges due the limited treatment options available. In study, we conducted genome-wide CRISPR–Cas9 screening presence inducer (RSL3) identify key driver genes involved ferroptosis. We identified ALOX15, lipoxygenase (LOX), as an essential Small activating RNA (saRNA) was used mediate expression ALOX15 promoted GBM cells. then coated saALOX15-loaded mesoporous polydopamine (MPDA) with Angiopep-2-modified macrophage membranes (MMs) reduce clearance by mononuclear phagocyte system (MPS) increase ability complex cross blood–brain barrier (BBB) during specific targeted therapy orthotopic GBM. These generated hybrid nanoparticles (NPs) induced mediating mitochondrial dysfunction rendering morphology abnormal. vivo, modified MM enabled NPs target cells, exert marked inhibitory effect on progression, promote radiosensitivity. Our results reveal promising suggest biomimetic strategy that depends biological properties MMs enhance vivo performance for treating

Language: Английский

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