Abstract 1389: Exploiting inherent DNA damage repair defects in IDH1/2 mutated gliomas with the CNS penetrant PARP inhibitor, pamiparib

2020 ◽  
Author(s):  
Christopher Hong ◽  
Amrita Sule ◽  
Jason Beckta ◽  
Ranjini Sundaram ◽  
Ranjit Bindra
Keyword(s):  
Dna Damage ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Damage Repair

scholarly journals Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

2019 ◽  
Vol 20 (19) ◽  
pp. 4728 ◽  
Author(s):  
Hwani Ryu ◽  
Hyun-Kyung Choi ◽  
Hyo Jeong Kim ◽  
Ah-Young Kim ◽  
Jie-Young Song ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Class Iii ◽  
Damage Repair ◽  
Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

scholarly journals Targeted DNA Damage Repair CRISPR/Cas9 Knockout Screen Identifies Novel Classification of Poly-ADP Ribose Polymerase Inhibitors Based on Key Base Excision Repair Proteins

2020 ◽  
Author(s):  
Gregory A. Breuer ◽  
Jonathan Bezney ◽  
Nathan R. Fons ◽  
Ranjini K. Sundaram ◽  
Wanjuan Feng ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Parp Inhibition ◽  
Brca1 And Brca2 ◽  
Damage Repair ◽  
Base Excision

ABSTRACTDNA repair deficiencies have become an increasingly promising target for novel therapeutics within the realm of clinical oncology. Recently, a number of inhibitors of Poly(ADP-ribose) Polymerases (PARPs) have received approval for the treatment of ovarian cancers with and without deleterious mutations in the homologous recombination proteins BRCA1 and BRCA2. Unfortunately, as over a hundred clinical trials are actively underway testing the utility of PARP inhibition across dozens of unique cancers, the mechanism of action for such inhibitors remains unclear. While many believe PARP trapping to be the most important determinant driving the cytotoxicity found in such inhibitors, clinically effective inhibitors exist which possess both strong and weak PARP-trapping qualities. Such results indicate that characterization of inhibitors as strong and weak trappers does not properly capture the intra-class characteristics of such small molecule inhibitors. Using a novel, targeted DNA damage repair and response (DDR) CRISPR/Cas9 screening library, we describe a new classification scheme for PARP inhibitors that revolves around sensitivity to key modulators of the base excision repair (BER) pathway, unrelated to trapping ability or catalytic inhibition of PARP. These findings demonstrate that inhibition of PARylation and induction of PARP trapping are not the only factors responsible for the clinical response of DDR-deficient cancers to PARP inhibition, and provide insight into the optimal choice of PARP inhibitor to be used in the setting of additional DNA repair deficiencies.

scholarly journals Suppression of isoprenylcysteine carboxylmethyltransferase compromises DNA damage repair

2021 ◽  
Vol 4 (12) ◽  
pp. e202101144
Author(s):  
Jingyi Tang ◽  
Patrick J Casey ◽  
Mei Wang
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Negative Impact ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Mapk Signaling ◽  
Cancer Therapies ◽  
Damage Repair ◽  
Isoprenylcysteine Carboxylmethyltransferase

DNA damage is a double-edged sword for cancer cells. On the one hand, DNA damage–induced genomic instability contributes to cancer development; on the other hand, accumulating damage compromises proliferation and survival of cancer cells. Understanding the key regulators of DNA damage repair machinery would benefit the development of cancer therapies that induce DNA damage and apoptosis. In this study, we found that isoprenylcysteine carboxylmethyltransferase (ICMT), a posttranslational modification enzyme, plays an important role in DNA damage repair. We found that ICMT suppression consistently reduces the activity of MAPK signaling, which compromises the expression of key proteins in the DNA damage repair machinery. The ensuing accumulation of DNA damage leads to cell cycle arrest and apoptosis in multiple breast cancer cells. Interestingly, these observations are more pronounced in cells grown under anchorage-independent conditions or grown in vivo. Consistent with the negative impact on DNA repair, ICMT inhibition transforms the cancer cells into a “BRCA-like” state, hence sensitizing cancer cells to the treatment of PARP inhibitor and other DNA damage–inducing agents.

scholarly journals PARP inhibitor Olaparib overcomes Sorafenib resistance through reshaping the pluripotent transcriptome in hepatocellular carcinoma

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xiao-Dong Yang ◽  
Fan-En Kong ◽  
Ling Qi ◽  
Jia-Xin Lin ◽  
Qian Yan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Damage ◽  
Stem Cell ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Embryonic Stem ◽  
Hepatic Differentiation ◽  
Sorafenib Treatment ◽  
Damage Repair ◽  
Stem Cell Pluripotency

AbstractHepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.

scholarly journals FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Shu-Ping Wang ◽  
Shi-Qi Wu ◽  
Shi-Hui Huang ◽  
Yi-Xuan Tang ◽  
Liu-Qiong Meng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Dna Damage ◽  
Triple Negative Breast Cancer ◽  
Cell Cycle Progression ◽  
Triple Negative ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Cycle Progression ◽  
Damage Repair

AbstractInducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

scholarly journals Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma

2020 ◽  
Vol 52 (2) ◽  
pp. 634-644 ◽  
Author(s):  
Min Chul Choi ◽  
Sohyun Hwang ◽  
Sewha Kim ◽  
Sang Geun Jung ◽  
Hyun Park ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Disease Free Survival ◽  
Serous Carcinoma ◽  
High Grade ◽  
Repair Gene ◽  
Damage Repair ◽  
Repair Genes

PurposeIn this study, we investigated the frequencies of mutations in DNA damage repair genes including <i>BRCA1</i>, <i>BRCA2</i>, homologous recombination genes and <i>TP53</i> gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic <i>BRCA</i> mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors.Materials and MethodsTissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and <i>TP53</i> gene and their relationships with patient survival were examined. Additionally, we analyzed <i>BRCA</i> germline variants in blood samples from 47 of the patients for comparison.Results<i>BRCA1</i>, <i>BRCA2</i>, and <i>TP53</i> mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in <i>RAD50, ATR, MSH6, MSH2</i>, and <i>FANCA</i> were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic <i>BRCA</i> mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without <i>TP53</i>mutation, exhibited better disease-free survival than those with <i>TP53</i> mutation alone.ConclusionDNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic <i>BRCA</i> mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5038-5038
Author(s):  
Jose Mauricio Mota ◽  
Ethan Barnett ◽  
Jones Nauseef ◽  
Konrad Hermann Stopsack ◽  
Andreas Georg Wibmer ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Dna Damage ◽  
Parp Inhibitor ◽  
Dna Damage Repair ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Damage Repair ◽  
Platinum Based Chemotherapy ◽  
Before And After ◽  
Repair Genes

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.

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