In vivo PDX CRISPR/Cas9 screens reveal mutual therapeutic targets to overcome heterogeneous acquired chemo-resistance

Leukemia, Journal Year: 2022, Volume and Issue: 36(12), P. 2863 - 2874

Published: Nov. 4, 2022

Abstract Resistance towards cancer treatment represents a major clinical obstacle, preventing cure of patients. To gain mechanistic insights, we developed model for acquired resistance to chemotherapy by treating mice carrying patient derived xenografts (PDX) acute lymphoblastic leukemia with widely-used cytotoxic drugs 18 consecutive weeks. In two distinct PDX samples, tumors initially responded treatment, until stable disease and eventually tumor re-growth evolved under therapy, at highly similar kinetics between replicate mice. Notably, different mutations in TP53 individual sets chromosomal alterations, suggesting independent parallel clonal evolution rather than selection, driven combination stochastic deterministic processes. Transcriptome proteome showed shared dysregulations providing putative targets overcome resistance. vivo CRISPR/Cas9 dropout screens revealed broad dependency on BCL2 , BRIP1 COPS2 . Accordingly, venetoclax re-sensitized derivative chemotherapy, despite genomic heterogeneity, demonstrating direct translatability the approach. Hence, presence multiple resistance-associated effective rescue polychemotherapy-resistant can be identified using functional testing preclinical models.

Language: Английский

---

Functional analyses of rare germline BRCA1 variants by transcriptional activation and homologous recombination repair assays

BMC Cancer, Journal Year: 2023, Volume and Issue: 23(1)

Published: April 21, 2023

Abstract Background Damaging alterations in the BRCA1 gene have been extensively described as one of main causes hereditary breast and ovarian cancer (HBOC). can lead to impaired homologous recombination repair (HRR) double-stranded DNA breaks, a process which involves RING, BRCT coiled-coil domains protein. In addition, protein is involved transcriptional activation (TA) several genes through its C-terminal domain. Methods this study, we investigated effect on HRR TA 11 rare missense variants classified uncertain clinical significance (VUS), located within or close proximity domain, with aim generating additional knowledge guide correct classification these variants. The were selected from our previous study “ Norway”, collection all detected at four medical genetic departments Norway. Results All variants, except one, showed significantly reduced activity compared wild type (WT) Two (p.Ala1708Val p.Trp1718Ser) also exhibited low similar pathogenic controls. variant p.Trp1718Ser could be reclassified likely pathogenic. However, for ten total strength evidence was not sufficient reclassification according CanVIG-UK BRCA1/BRCA2 - specific guidelines interpretation. Conclusions When including newly achieved functional other available information, VUS Eight affected only assessed activities BRCA1, highlighting importance comparing results obtained assays better understand consequences function. This especially important multifunctional proteins such BRCA1.

Language: Английский

---

Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review)

Oncology Reports, Journal Year: 2022, Volume and Issue: 48(4)

Published: Aug. 19, 2022

Genomic instability, a feature of most cancers, contributes to malignant cell transformation and cancer progression due the accumulation genetic alterations. instability is reflected at numerous levels, from single nucleotide chromosome levels. However, exact molecular mechanisms regulators genomic in remain unclear. Growing evidence indicates that binding long non‑coding RNAs (lncRNAs) protein chaperones confers variety regulatory functions, including managing instability. The aim present review was examine roles mitosis, telomeres, DNA repair, epigenetics by which lncRNAs regulate them proteins cells. This our understanding role can potentially provide entry points targets for therapies.

Language: Английский

---

Detection of BRCA1/2 pathogenic variants in patients with breast and/or ovarian cancer and their families. Analysis of 3,458 cases from Lower Silesia (Poland) according to the diagnostic algorithm of the National Cancer Control Programme

Frontiers in Genetics, Journal Year: 2022, Volume and Issue: 13

Published: Sept. 12, 2022

Breast and ovarian cancers are among the most common malignancies in female population, with approximately 5-10% of cases being hereditary. BRCA1 BRCA2 other homologous recombination genes tested hereditary breast cancer (HBOC) patients. As next-generation sequencing (NGS) has become a standard popular technique, such as for HBOC, it greatly simplified accelerated molecular diagnosis cancer. The study group included 3,458 HBOC patients or their relatives from Lower Silesia (Poland) (a voivodeship located south-west Poland inhabited by 2.9 million people). All were according to recommendations National Cancer Control Programme Ministry Health years 2018-21. We 3,400 recurrent pathogenic variants Polish population: five founder (c.5266dup, c.181T>G, c.4035del, c.3700_3704del, c.68_69del), two PALB2 (c.509_510del, c.172_175del) three CHEK2 [c.1100del, c.444+1G>A, g.27417113-27422508del (del5395)]. Next 260 chosen BRCA1/2 NGS panel, additionally selected marker using Sanger MLPA methods 45 13 individuals, respectively. analysis revealed 144 carriers 37 different (22 15 BRCA2). Among all detected variants, 71.53% constituted variants. Our that Silesian first-line test may be limited only BRCA1-c.5266dup, c.4035del-but aim should provide full screening critical genes. key still growing role diagnostics neoplasms, which includes is undeniable. Therefore, necessary complete optimal therapeutic prophylactic algorithms line current medical knowledge.

Language: Английский

---

Prevalence of Homologous Recombination Deficiency in First-Line PARP Inhibitor Maintenance Clinical Trials and Further Implication of Personalized Treatment in Ovarian Cancer

Cancers, Journal Year: 2023, Volume and Issue: 15(12), P. 3095 - 3095

Published: June 7, 2023

Among ovarian cancer patients with BRCA mutation or homologous recombination deficiency (HRD), the efficacy of Poly-ADP-ribose polymerase (PARP) inhibitors such as olaparib, niraparib, veliparib, and rucaparib has been proven in a number clinical trials. HRD are currently indicated for PARP inhibitor maintenance treatment cancer. diagnostic tests examine various components, resulting different status definitions and, result, decisions. A exist, but test results provided by companies may differ they use methods cutoffs. prevalence difference was shown between It is important to select an appropriate method that can present accurate phenotypes predict sensitivity so who most likely benefit from selected. Additionally, subset data trials, there race higher Japanese Chinese shown. Further large-scale investigations on racial differences needed this contribute changes determining plan personalized patients.

Language: Английский

---