Current Opinion in Genetics & Development, Journal Year: 2025, Volume and Issue: 92, P. 102325 - 102325
Published: March 4, 2025
Language: Английский
Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(14)
Published: July 14, 2024
Mutations in the tumor-suppressor genes BRCA1 and BRCA2 resulting BRCA1/2 deficiency are frequently identified breast, ovarian, prostate, pancreatic, other cancers. Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cancer cells by inducing synthetic lethality, providing an effective biomarker-guided strategy for targeted therapy. However, a substantial fraction of patients carrying mutations do not respond to PARPis, most develop resistance PARPis over time, highlighting major obstacle PARPi therapy clinic. Recent studies have revealed that changes specific functional defects cells, particularly their suppressing protecting single-stranded DNA gaps, contribute gain or loss PARPi-induced lethality. These findings only shed light on mechanism action but also lead revised models explain how BRCA-deficient cells. Furthermore, new mechanistic principles sensitivity emerged from these studies, generating potentially useful guidelines predicting response design therapies overcoming resistance. In this Review, we will discuss recent put them context with classic views aiming stimulate development therapeutic strategies overcome improve
Language: Английский
Citations
13
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: May 24, 2024
Abstract Histone H2AX plays a key role in DNA damage signalling the surrounding regions of double-strand breaks (DSBs). In response to damage, becomes phosphorylated on serine residue 139 (known as γH2AX), resulting recruitment repair effectors 53BP1 and BRCA1. Here, by studying resistance poly(ADP-ribose) polymerase (PARP) inhibitors BRCA1/2-deficient mammary tumours, we identify function for γH2AX orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven degradation is elicited suppressing CtIP-mediated protection. As result, loss restores stability increases chemoresistance tumour cells without restoring homology-directed repair, highlighted lack damage-induced RAD51 foci. Furthermore, attempt discover acquired genetic vulnerabilities, find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) H2AX-deficient tumours interfering with summary, our results demonstrate biology BRCA-deficient establish separable from its classical DSB repair.
Language: Английский
Citations
12
Trends in cancer, Journal Year: 2024, Volume and Issue: 10(9), P. 857 - 869
Published: July 14, 2024
In recent years, various poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) have been approved for the treatment of several cancers to target vulnerability homologous recombination (HR) deficiency (e.g., due BRCA1/2 dysfunction). this review we analyze ongoing debates and breakthroughs in use PARPis BRCA1/2-deficient cancers, juxtaposing 'double-strand break (DSB)' 'single-stranded DNA (ssDNA) gap' models synthetic lethality induced by PARPis. We spotlight complexity interaction, highlighting emerging research on role theta (POLθ) ssDNA gaps shaping therapy responses. scrutinize clinical ramifications these findings, especially concerning PARPi efficacy resistance mechanisms, underscoring heterogeneity BRCA-mutated tumors urgent need advanced bridge gap between laboratory patient outcomes.
Language: Английский
Citations
10
Nature, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 19, 2025
Language: Английский
Citations
1
Trends in Genetics, Journal Year: 2024, Volume and Issue: 40(9), P. 757 - 771
Published: May 23, 2024
The tumour-suppressive roles of BRCA1 and 2 have been attributed to three seemingly distinct functions - homologous recombination, replication fork protection, single-stranded (ss)DNA gap suppression their relative importance is under debate. In this review, we examine the origin resolution ssDNA gaps discuss recent advances in understanding role BRCA1/2 suppression. There are ample data showing that accumulation BRCA1/2-deficient cells linked genomic instability chemosensitivity. However, it remains unclear whether there a causative function cannot unambiguously be dissected from other functions. We therefore conclude closely intertwined not mutually exclusive.
Language: Английский
Citations
5
Cancer Control, Journal Year: 2024, Volume and Issue: 31
Published: Jan. 1, 2024
The application of PARP inhibitors has revolutionized cancer treatment and achieved significant advancements, particularly with regard to tumors defects in genes involved homologous recombination repair (HRR) processes, such as BRCA1 BRCA2. Despite the promising outcomes inhibitors, certain limitations challenges still exist, including acquired drug resistance, severe side effects, limited therapeutic benefits for patients without deficiency (HRD). Various combinations involving have been developed overcome these limitations. Among these, immune checkpoint antiangiogenic agents, various small-molecule are well-studied strategies that show great potential optimizing efficacy overcoming resistance mechanisms, expanding target populations. However, efficiency overlapping toxicity combination cancers vary among studies, thereby limiting their use. In this review, we describe mechanisms better understand treatments. Furthermore, summarized recent studies on a range medications discussed clinical efficacy. objective review is enhance comprehensiveness information pertaining topic.
Language: Английский
Citations
5
Cell Reports, Journal Year: 2024, Volume and Issue: 43(11), P. 114964 - 114964
Published: Nov. 1, 2024
Language: Английский
Citations
5
Deleted Journal, Journal Year: 2025, Volume and Issue: 33(1), P. 200934 - 200934
Published: Jan. 14, 2025
The development of poly (ADP-ribose) polymerase inhibitors (PARPis) is widely considered a therapeutic milestone in the management BRCA1/2-deficient malignancies. Since growing number cancer treatment guidelines include PARPis, inevitably emerging PARPi resistance becomes serious limitation that must be addressed. Targeting DNA damage response signaling kinase, ATR (ataxia telangiectasia and rad3-related serine/threonine kinase), activated to PARPi-induced replication stress, represents promising approach fighting PARPi-resistant cancers. success this combination therapy preclinical models has inspired efforts translate its potential through extensive clinical research trials. However, available evidence suggests PARPi/ATRi combinations have yet reach their anticipated potential. In review, we summarize work elucidating mechanisms underpinning effectiveness ATRi review translational studies reporting efficacy different types cancer. Finally, discuss biomarkers patient selection for customized treatments.
Language: Английский
Citations
0
Biochemical Society Transactions, Journal Year: 2025, Volume and Issue: 53(01)
Published: Feb. 10, 2025
The introduction of poly-ADP ribose polymerase (PARP) inhibitors (PARPi) has completely changed the treatment landscape breast cancer susceptibility 1–2 (BRCA1–BRCA2)-mutant cancers and generated a new avenue research in fields DNA damage response therapy. Despite this, primary secondary resistances to PARPi have become challenge clinic, novel therapies are urgently needed address this problem. After two decades research, unifying model explaining sensitivity cells is still missing. Here, we review current knowledge field increasing evidence pointing crucial role for replicative gaps mediating sensitization BRCA-mutant ‘wild-type’ cells. Finally, discuss challenges be addressed further improve utilization tackle emergence resistance clinical context.
Language: Английский
Citations
0
Molecular and Cellular Biochemistry, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 21, 2025
Language: Английский
Citations
0