PARP1 mutation

PARP inhibitors may be considered for patients with advanced pancreatic cancer harboring pathogenic alterations of BRCA who cannot tolerate standard chemotherapy. Maintenance PARPis can be considered in selected patients with non-BRCA/non-PALB2 HRR mutations.

This study discovered a new type of PTM of PARP1 in CC, and showed that PARP1 acetylation at K119 is essential in regulating the proliferation and progression of CC through ERK1/2. Further studies are required to investigate how PARP1 acetylation impact its function.

IU1-248 promotes NHEJ repair through the downregulation of the expression of c-Myc. USP14 inhibition may be a plausible strategy for expanding the utility of PARG inhibitors in TNBC in BRCA-mutant, PARP inhibitor-resistant settings.

PARPi-resistant aBC represents a clinical unmet need due to the lack of specific targeted therapies and validated prognostic and predictive biomarkers. Constant efforts are required to better define the mechanisms of PARPi resistance and, consequently, develop biomarker-based treatment approach to prevent or overcame resistance.

Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.

This genome wide characterization of premalignant PVL identifies both known and potentially novel oncogenic mechanisms in this disorder.

No differences in survival outcomes were observed among patients with different BRCA statuses. Furthermore, for patients who had undergone two or more lines of chemotherapy before PARP inhibitor maintenance therapy, no negative effects of PARP inhibitors on subsequent treatment were found, regardless of BRCA status.

Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer.

These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Collaborative efforts between medical professionals, researchers, and AI experts are vital for unlocking AI's potential to enhance pancreatic cancer care. In conclusion, despite the challenges, advancements in liquid biopsies, precision medicine, and AI offer hope for enhancing the diagnosis, treatment, and management of pancreatic cancer.

Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

The median age at the time of diagnosis was 50 years (range 45-73), all patients underwent a minimum of 2 lines of standard chemotherapy (including at least 1 platinum-based regimen) before PARP-i oral maintenance; 10 patients (58%) had been exposed to Olaparib, 5 (29.5%) to Niraparib and 2 (11.5%) to Rocuraparib. Recurrent molecular alterations were not found in our patients. Our data show how MN-pCT occurring after the combination of platinum-based chemotherapy and PARP-i oral maintenance share common cytogenetic alterations, mostly involving chromosome 5 and 7, and NGS-detectable mutations.

For chemonaive patients, drugs that helps in efflux of reduced glutathione or prevent the redox coupling of GSH-GSSG, like Cisplatin, could be considered as the best therapeutic choice for HGSOC. For patients with BRCA1/2 mutations, PARP inhibitors alone or with Bevacizumab can be effective. Immune checkpoint inhibitors could be effective against immunoreactive subtypes. Identification of genes deregulated in chemoresistance could provide better insights in dealing with the disease.

We show that HRP restoration and RAD51 foci in advanced BRCA1/2m breast cancers is the dominant form resistance to HRD-targeted treatment. We also demonstrate for the first time that analysis of DNA replication fork dynamics can be carried out in breast cancer PDOs and could be further explored as a functional predictive biomarker of PARPi resistance. 1.Pellegrino et al, 2022 (PMID: 35425960) 2.Chaudhuri et al, 2016 (PMID: 27443740)

In addition, we found that the PARP1 SUMOylation-mediated NF-κB pathway activation is a positive regulatory mechanism in the tumorigenesis of AML. These findings may provide potential clinical implications for AML treatment.

The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation.

Here, we evaluate anti-leukemic potential of PARPi, understand subtype dependent differential responses, discuss recent clinical trials and provide an outlook for future combination therapy strategies. Extensive genetic and epigenetic characterization, utilizing results from completed and ongoing studies will further help to determine specific subset of patients who may respond, and establish PARPi as a mainstay in leukemia treatment.

Following the FDA approval of Olaparib in 2014 for the treatment of BRCA mutated ovarian cancer, other chemically distinct small molecules have entered clinical trials...Excitingly, the next generation of PARP1 inhibitors have the potential to offer dramatic therapeutic improvements in patients with homologous recombination deficiencies (HRD). The evolution of PARP inhibitors from non-selective, non-trapper to the highly selective PARP1 molecules will be discussed.

ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1-USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.

In conclusion, these lymphoid cell lines have different lesion profiles and sensitivity to Niraparib. In the future, a better characterization of compensatory repair pathways (including BRCA1 mutations and homologous repair efficiency) may help identify patients who will benefit from therapy with PARP1/2 inhibitors, as niraparib. Targeted therapy, Apoptosis, DNA damage, Lymphoid malignancy

Together, these findings suggest an unrecognized prognostic and therapeutic role of PARP-1 in iCCA patients with oncogenic KRAS signaling and unveil the potential mechanism of PARP1 regulation by CHK1 kinase.

Together, these findings suggest an unrecognized prognostic and therapeutic role of PARP-1 in iCCA patients with oncogenic KRAS signaling and unveil the potential mechanism of PARP-1 regulation by CHK1 kinase.

In addition, we employed GBM PDX models for checkpoint-inhibitor sensitivity in humanized mouse settings. Drug testing was performed in s.c. and orthotopic models revealed, that best treatment responses in s.c. models (tumor growth inhibition > 50%) were observed for SoC temozolomide (TMZ), irinotecan and bevacizumab...Further, treatment of GBM PDX with ipilimumab, nivolumab or pembrozolumab generated minor growth delay. In drug sensitivity screening, irinotecan or bevacizumab were identified as alternative treatment options in TMZ resistant GBM PDX models. In drug sensitivity screening, irinotecan or bevacizumab were identified as alternative treatment options in TMZ resistant GBM PDX models. Our data demonstrate, that the established platform of s.c. and orthotopic GBM PDX is valuable for drug development and can well be complemented by a PDX-derived cell lines for in vitro screens. Furthermore, these models can be used for the evaluation of new immune-oncology therapies.

P1/2, N=45, Not yet recruiting, Huihua Xiong

This review also summarizes the current clinical trial landscape associated with the therapeutic utility of epigenetics in low-grade gliomas. Much of the evidence currently remains restricted to preclinical studies, warranting further investigation to demonstrate true clinical utility.

P1, N=120, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=120, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Dec 2022 --> Dec 2023

This model will then be applied to compound mutations, including patients that carry rare population mutations to allow accurate variant interpretation in understudied minorities. Combined, these studies will provide detailed variant annotations for this important cancer gene and provide variant specific recommendations for overcoming resistance in clinical sequencing, with direct translation to clinical care through linkages from MAVEDB to clinical annotation databases.

Moreover, these mechanisms of action significantly correlated with the side-effect-producing mechanisms of BRCA mutations and PARPi. In conclusion, natural phytochemicals may be effective in alleviating the side effects of BRCA mutant ovarian cancer cells and PARP inhibitors.

Inhibiting PARP has evolved for triggering cell damage in cancerous cells when paired with certain other anticancer drugs including temozolomide (TMZ)...This article analyzes the justification and clinical evidence for PARPi in glioma to offer potential therapeutic approaches. Despite the effectiveness of these targeted drugs, researchers have looked into a number of resistance mechanisms as well as the growing usage of PARPi in clinical practice for the treatment of various malignancies.

SRSF2P95H and SF3B1K700E cells showed increased sensitivity to olaparib and rucaparib (Fig. In summary, this study provides a pre-clinical rationale for therapeutic targeting of PARP1 in SF-mutant leukemia. Moreover, PARP and ATR inhibitor combination could emerge as a new therapeutic strategy in this genetically distinct disease subtype.

Furthermore, NN3 showed potent activity and low toxicity in vivo. In conclusion, we propose PROTAC-mediated degradation of PARP1 as a novel strategy against mutation-related PARPi resistance and a paradigm for targeting breast cancer with functional p53 via ferroptosis induction.

PARP1 may serve as an important biological marker to predict the therapeutic effect of immune checkpoint inhibitors and evaluate the prognosis of patients with ccRCC with polybromo 1 mutation. Therefore, the roles of DDR pathway on RCC progression or treatment may hold promises for the treatment of certain specific types of RCC.

No abstract available

Our integrative analysis reveals mechanistic insight into the role of SF3B1 mutations in endocrine therapy response in ER+ breast cancers, where altered SF3B1 induces ER- transcriptional re-programming. We further identified a robust synthetic-lethal relationship of mutant SF3B1 with PARP inhibition that is caused by a defective response to PARPi induced replication stress. Furthermore, we identified several potential selective combination strategies together with PARPi that are selective for SF3B1MUT cells.

Patients receive vudalimab 10 mg/kg intravenously every 2 weeks plus either carboplatin AUC 4/cabazitaxel 20 mg/m 2 (or docetaxel 60 mg/m 2 , if chemotherapy naïve) every 3 weeks (Cohorts 1, 2, 5; n=20 each) or olaparib 300 mg 2x/day (Cohort 3; n=20), or as monotherapy (Cohort 4; n=5). Preliminary safety and activity data will be presented. Trial Registration NCT05005728

Prexasertib demonstrated durable single agent activity in a subset of patients with recurrent ovarian cancer regardless of clinical characteristics, BRCA status, or prior therapies, including PARPi. There was no obvious correlation with genomic alterations in responders vs non-responders, emphasizing the need for alternative biomarker approaches for responder identification.

Our findings suggest that the mutated PARG acquires PDD00017273 resistance due to structural modifications. In addition, our findings indicate that PDD00017273 resistance induces mutation and PARP downregulation. These discoveries collectively provide a better understanding of the anticancer candidate PARG inhibitors in terms of resistance mechanisms and anticancer strategies.

In this review, we discuss the underlying molecular mechanisms of PARP inhibitors and the results from the clinical studies that investigated the effects of the FDA-approved PARP inhibitors olaparib, rucaparib, and niraparib. We also review the current research progress on PARP inhibitors, their safety, and their combined usage with antiangiogenic agents. Nevertheless, many unknown aspects of PARP inhibitors, including detailed mechanisms of actions, along with the effectiveness and safety of the treatment of EOCs, warrant further investigation.

P=N/A, N=100, Recruiting, Yonsei University

When bevacizumab can be added to chemotherapy, progression-free survival improves significantly...This review describes some of the challenges in treating patients with platinum resistance and suggests refinements in the selection of patients most likely to benefit from targeting a DNA damage response, angiogenesis or immune modulation. It also describes novel agents of interest and possible mechanisms of the synergy of therapeutic combinations.

Hagiwara, European Urology 2021 2. Motzer, Cancer Cell 2020