Kidney International, Год журнала: 2023, Номер 105(1), С. 115 - 131
Опубликована: Окт. 31, 2023
Язык: Английский
Genes & Development, Год журнала: 2022, Номер 36(5-6), С. 278 - 293
Опубликована: Март 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.
Язык: Английский
Процитировано
120
MedComm, Год журнала: 2022, Номер 3(4)
Опубликована: Окт. 13, 2022
Compared with traditional therapies, targeted therapy has merits in selectivity, efficacy, and tolerability. Small molecule inhibitors are one of the primary therapies for cancer. Due to their advantages a wide range targets, convenient medication, ability penetrate into central nervous system, many efforts have been devoted developing more small inhibitors. To date, 88 approved by United States Food Drug Administration treat cancers. Despite remarkable progress, cancer treatment still face obstacles, such as low response rate, short duration response, toxicity, biomarkers, resistance. better promote development targeting cancers, we comprehensively reviewed involved all agents pivotal drug candidates clinical trials arranged signaling pathways classification We discussed lessons learned from these agents, proper strategies overcome resistance arising different mechanisms, combination concerned Through our review, hoped provide insights perspectives research treatment.
Язык: Английский
Процитировано
87
Autophagy, Год журнала: 2023, Номер 19(7), С. 2062 - 2077
Опубликована: Фев. 8, 2023
Ferroptosis is a newly characterized form of programmed cell death, which driven by the lethal accumulation lipid peroxides catalyzed intracellular bioactive iron. Targeted induction ferroptotic death holds great promise for therapeutic design against other therapy-resistant cancers. To date, multiple post-translational modifications have been elucidated to impinge on sensitivity. Here we report that Ser/Thr protein kinase ATM, major sensor DNA double-strand break damage, indispensable ferroptosis execution. Pharmacological inhibition or genetic ablation ATM significantly antagonizes ferroptosis. Besides, ablation-induced resistance largely independent its downstream target TRP53, as cells defective in both Trp53 and Atm are still more insensitive inducers than trp53 single knockout cells. Mechanistically, dominates labile free iron phosphorylating NCOA4, facilitating NCOA4-ferritin interaction therefore sustaining ferritinophagy, selective type macroautophagy/autophagy specifically degrading ferritin recycling. Our results thus uncover novel regulatory circuit comprising ATM-NCOA4 orchestrating ferritinophagy bioavailability.
Язык: Английский
Процитировано
77
Cancer Discovery, Год журнала: 2023, Номер 13(7), С. 1521 - 1545
Опубликована: Апрель 7, 2023
Genomic stability in normal cells is crucial to avoid oncogenesis. Accordingly, multiple components of the DNA damage response (DDR) operate as bona fide tumor suppressor proteins by preserving genomic stability, eliciting demise with unrepairable lesions, and engaging cell-extrinsic oncosuppression via immunosurveillance. That said, DDR sig-naling can also favor progression resistance therapy. Indeed, signaling cancer has been consistently linked inhibition tumor-targeting immune responses. Here, we discuss complex interactions between inflammation context oncogenesis, progression, Accumulating preclinical clinical evidence indicates that intimately connected emission immunomodulatory signals malignant cells, part a program preserve organismal homeostasis. DDR-driven inflammation, however, have diametrically opposed effects on immunity. Understanding links may unlock novel immunotherapeutic paradigms treat cancer.
Язык: Английский
Процитировано
55
Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)
Опубликована: Сен. 8, 2023
Genome instability has been identified as one of the enabling hallmarks in cancer. DNA damage response (DDR) network is responsible for maintenance genome integrity cells. As cancer cells frequently carry DDR gene deficiencies or suffer from replicative stress, targeting processes could induce excessive damages (or unrepaired DNA) that eventually lead to cell death. Poly (ADP-ribose) polymerase (PARP) inhibitors have brought impressive benefit patients with breast (BRCA) mutation homologous recombination deficiency (HRD), which proves concept synthetic lethality treatment. Moreover, other two scenarios inhibitor application, replication stress and combination chemo- radio- therapy, are under active clinical exploration. In this review, we revisited progress therapy beyond launched first-generation PARP inhibitors. Next generation PARP1 selective inhibitors, maintain efficacy while mitigating side effects, may diversify application clinic. Albeit unavoidable on-mechanism toxicities, several small molecules checkpoints (gatekeepers) shown great promise preliminary results, warrant further evaluations. addition, repair pathways (caretakers) also preclinical development. With these progresses efforts, envision a new wave innovations within come age.
Язык: Английский
Процитировано
53
Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(14), С. 11488 - 11521
Опубликована: Июль 2, 2024
In recent years, synthetic lethality has been recognized as a solid paradigm for anticancer therapies. The discovery of growing number lethal targets led to significant expansion in the use lethality, far beyond poly(ADP-ribose) polymerase inhibitors used treat BRCA1/2-defective tumors. particular, molecular within DNA damage response have provided source that rapidly reached clinical trials. This Perspective focuses on most progress and their inhibitors, response, describing design associated therapeutic strategies. We will conclude by discussing current challenges new opportunities this promising field research, stimulate discussion medicinal chemistry community, allowing investigation reach its full potential.
Язык: Английский
Процитировано
16
Journal of Agricultural and Food Chemistry, Год журнала: 2024, Номер 72(12), С. 6660 - 6671
Опубликована: Март 19, 2024
Background: Deoxynivalenol (DON) contamination, pervasive throughout all stages of food production and processing, presents a significant threat to human health. The degradation ferritin mediated by nuclear receptor coactivator 4 (NCOA4), termed ferritinophagy, plays crucial role in maintaining iron homeostasis regulating ferroptosis. Aim: This study aims elucidate the ferritinophagy ferroptosis DON-induced liver injury. Methods: Male mice AML12 cells were subjected varying doses DON, serving as vivo vitro models, respectively. Protein expression was assessed using immunofluorescence western blot techniques. Co-immunoprecipitation employed investigate protein–protein interactions. Results: Our findings demonstrate that DON triggers hepatocyte ferritinophagy-dependent manner. Specifically, impedes activation mammalian target rapamycin complex 1 (mTORC1) inhibiting RAC1's binding mTOR, thereby ultimately inducing autophagy. Concurrently, amplifies NCOA4's affinity for facilitating NCOA4 phosphorylation through ataxia-telangiectasia mutated kinase (ATM), thus promoting autophagy-dependent ferritin. Both autophagy inhibition suppression ameliorate Conclusion: concludes facilitates NCOA4-mediated via ATM–NCOA4 pathway, subsequently liver.
Язык: Английский
Процитировано
15
Journal of Hematology & Oncology, Год журнала: 2022, Номер 15(1)
Опубликована: Окт. 17, 2022
Abstract Continuous cell division is a hallmark of cancer, and the underlying mechanism tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly maintaining genome stability during division. Based on their distinct functions in control, classified into two groups: DNA damage replication stress checkpoints. The (ATM-CHK2-p53) primarily monitor genetic errors arrest progression to facilitate repair. Unfortunately, genes involved frequently mutated human malignancies. In contrast, associated with (ATR-CHK1-WEE1) rarely tumors, cancer cells highly dependent these prevent catastrophe secure integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mutant repair pathways cells. However, increasing number patients acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that combination therapy targeting PARPs act synergistically increase errors, compromise machinery, disrupt cycle, thereby death rate deficiency or resistance. We highlight combinational strategy involving inhibition major checkpoint pathways, ATM-CHK2-TP53 ATR-CHK1-WEE1. biological functions, mechanisms against inhibitors, advances preclinical research, clinical trials also reviewed.
Язык: Английский
Процитировано
61
Molecular Cell, Год журнала: 2022, Номер 83(2), С. 167 - 185.e9
Опубликована: Дек. 27, 2022
Язык: Английский
Процитировано
41
Nature, Год журнала: 2023, Номер 616(7957), С. 504 - 509
Опубликована: Апрель 12, 2023
Язык: Английский
Процитировано
40