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1.
ChemMedChem ; : e202400013, 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38648251

ABSTRACT

Metastasis is responsible for about 90 % of cancer deaths. Anti-metastatic drugs, termed as migrastatics, offer a distinctive therapeutic approach to address cancer migration and invasion. However, therapeutic exploitation of metastasis-specific targets remains limited, and the effective prevention and suppression of metastatic cancer continue to be elusive. Lysophosphatidic acid receptor 1 (LPA1) is activated by an endogenous lipid molecule LPA, leading to a diverse array of cellular activities. Previous studies have shown that the LPA/LPA1 axis supports the progression of metastasis for many types of cancer. In this study, we report the synthesis and biological evaluation of fluorine-containing triazole derivatives as potent LPA1 antagonists, offering potential as migrastatic drugs for triple negative breast cancer (TNBC). In particular, compound 12 f, the most potent and highly selective in this series with an IC50 value of 16.0 nM in the cAMP assay and 18.4 nM in the calcium mobilization assay, inhibited cell survival, migration, and invasion in the TNBC cell line. Interestingly, the compound did not induce apoptosis in TNBC cells and demonstrated no cytotoxic effects. These results highlight the potential of LPA1 as a migrastatic target. Consequently, the LPA1 antagonists developed in this study hold promise as potential migrastatic candidates for TNBC.

2.
Transl Lung Cancer Res ; 13(3): 699-705, 2024 Mar 29.
Article in English | MEDLINE | ID: mdl-38601449
3.
Cancers (Basel) ; 15(21)2023 Oct 31.
Article in English | MEDLINE | ID: mdl-37958404

ABSTRACT

The success of PD-1/PD-L1-targeted therapy in lung cancer has resulted in great enthusiasm for additional immunotherapies in development to elicit similar survival benefits, particularly in patients who do not respond to or are ineligible for PD-1 blockade. CD47 is an immunosuppressive molecule that binds SIRPα on antigen-presenting cells to regulate an innate immune checkpoint that blocks phagocytosis and subsequent activation of adaptive tumor immunity. In lung cancer, CD47 expression is associated with poor survival and tumors with EGFR mutations, which do not typically respond to PD-1 blockade. Given its prognostic relevance, its role in facilitating immune escape, and the number of agents currently in clinical development, CD47 blockade represents a promising next-generation immunotherapy for lung cancer. In this review, we briefly summarize how tumors disrupt the cancer immunity cycle to facilitate immune evasion and their exploitation of immune checkpoints like the CD47-SIRPα axis. We also discuss approved immune checkpoint inhibitors and strategies for targeting CD47 that are currently being investigated. Finally, we review the literature supporting CD47 as a promising immunotherapeutic target in lung cancer and offer our perspective on key obstacles that must be overcome to establish CD47 blockade as the next standard of care for lung cancer therapy.

4.
Hepatology ; 77(3): 729-744, 2023 03 01.
Article in English | MEDLINE | ID: mdl-35302667

ABSTRACT

BACKGROUND AND AIMS: Prognosis of HCC remains poor due to lack of effective therapies. Immune checkpoint inhibitors (ICIs) have delayed response and are only effective in a subset of patients. Treatments that could effectively shrink the tumors within a short period of time are idealistic to be employed together with ICIs for durable tumor suppressive effects. HCC acquires increased tolerance to aneuploidy. The rapid division of HCC cells relies on centrosome duplication. In this study, we found that polo-like kinase 4 (PLK4), a centrosome duplication regulator, represents a therapeutic vulnerability in HCC. APPROACH AND RESULTS: An orally available PLK4 inhibitor, CFI-400945, potently suppressed proliferating HCC cells by perturbing centrosome duplication. CFI-400945 induced endoreplication without stopping DNA replication, causing severe aneuploidy, DNA damage, micronuclei formation, cytosolic DNA accumulation, and senescence. The cytosolic DNA accumulation elicited the DEAD box helicase 41-stimulator of interferon genes-interferon regulatory factor 3/7-NF-κß cytosolic DNA sensing pathway, thereby driving the transcription of senescence-associated secretory phenotypes, which recruit immune cells. CFI-400945 was evaluated in liver-specific p53/phosphatase and tensin homolog knockout mouse HCC models established by hydrodynamic tail vein injection. Tumor-infiltrated immune cells were analyzed. CFI-400945 significantly impeded HCC growth and increased infiltration of cluster of differentiation 4-positive (CD4 + ), CD8 + T cells, macrophages, and natural killer cells. Combination therapy of CFI-400945 with anti-programmed death-1 showed a tendency to improve HCC survival. CONCLUSIONS: We show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing antitumor immunity to achieve a durable suppressive effect even in late-stage mouse HCC.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Mice , Aneuploidy , Carcinoma, Hepatocellular/pathology , Cell Cycle , Cell Line, Tumor , Liver Neoplasms/pathology , Protein Serine-Threonine Kinases/metabolism
5.
Pharmaceutics ; 14(11)2022 Nov 19.
Article in English | MEDLINE | ID: mdl-36432707

ABSTRACT

Targeted drug and gene delivery using ultrasound and microbubbles (USMB) has the potential to treat several diseases. In vitro investigation of USMB-mediated delivery is of prime importance prior to in vivo studies because it is cost-efficient and allows for the rapid optimization of experimental parameters. Most in vitro USMB studies are carried out with non-clinical, research-grade ultrasound systems, which are not approved for clinical use and are difficult to replicate by other labs. A standardized, low-cost, and easy-to-use in vitro experimental setup using a clinical ultrasound system would facilitate the eventual translation of the technology to the bedside. In this paper, we report a modular 3D-printed experimental setup using a clinical ultrasound transducer that can be used to study USMB-mediated drug delivery. We demonstrate its utility for optimizing various cargo delivery parameters in the HEK293 cell line, as well as for the CMT167 lung carcinoma cell line, using dextran as a model drug. We found that the proportion of dextran-positive cells increases with increasing mechanical index and ultrasound treatment time and decreases with increasing pulse interval (PI). We also observed that dextran delivery is most efficient for a narrow range of microbubble concentrations.

6.
Sci Adv ; 8(36): eabq4293, 2022 09 09.
Article in English | MEDLINE | ID: mdl-36070391

ABSTRACT

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER+ breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER+ breast cancer patients who develop resistance to CDK4/6i.


Subject(s)
M Phase Cell Cycle Checkpoints , Neoplasms , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics
7.
Proc Natl Acad Sci U S A ; 119(32): e2119514119, 2022 08 09.
Article in English | MEDLINE | ID: mdl-35914158

ABSTRACT

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4+ T cells, and CD8+ T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Protein Kinase Inhibitors , Pyrazoles , Pyrimidines , Animals , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation , Killer Cells, Natural/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Mice , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases , Protein-Tyrosine Kinases/metabolism , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use
8.
Mol Cancer Ther ; 18(10): 1775-1786, 2019 10.
Article in English | MEDLINE | ID: mdl-31358662

ABSTRACT

The spindle assembly checkpoint maintains genomic integrity. A key component is tyrosine threonine kinase (TTK, also known as Mps1). TTK antagonism is hypothesized to cause genomic instability and cell death. Interrogating The Cancer Genome Atlas revealed high TTK expression in lung adenocarcinomas and squamous cell cancers versus the normal lung (P < 0.001). This correlated with an unfavorable prognosis in examined lung adenocarcinoma cases (P = 0.007). TTK expression profiles in lung tumors were independently assessed by RNA in situ hybridization. CFI-402257 is a highly selective TTK inhibitor. Its potent antineoplastic effects are reported here against a panel of well-characterized murine and human lung cancer cell lines. Significant antitumorigenic activity followed independent treatments of athymic mice bearing human lung cancer xenografts (6.5 mg/kg, P < 0.05; 8.5 mg/kg, P < 0.01) and immunocompetent mice with syngeneic lung cancers (P < 0.001). CFI-402257 antineoplastic mechanisms were explored. CFI-402257 triggered aneuploidy and apoptotic death of lung cancer cells without changing centrosome number. Reverse phase protein arrays (RPPA) of vehicle versus CFI-402257-treated lung cancers were examined using more than 300 critical growth-regulatory proteins. RPPA bioinformatic analyses discovered CFI-402257 enhanced MAPK signaling, implicating MAPK antagonism in augmenting TTK inhibitory effects. This was independently confirmed using genetic and pharmacologic repression of MAPK that promoted CFI-402257 anticancer actions. TTK antagonism exerted marked antineoplastic effects against lung cancers and MAPK inhibition cooperated. Future work should determine whether CFI-402257 treatment alone or with a MAPK inhibitor is active in the lung cancer clinic.


Subject(s)
Apoptosis/drug effects , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Polyploidy , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Anaphase/drug effects , Animals , Carcinogenesis/drug effects , Carcinogenesis/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Centrosome/drug effects , Centrosome/metabolism , Humans , Mice , Protein-Tyrosine Kinases/metabolism , Pyrazoles/pharmacology , Pyrimidines/pharmacology
9.
Proc Natl Acad Sci U S A ; 116(9): 3604-3613, 2019 02 26.
Article in English | MEDLINE | ID: mdl-30733286

ABSTRACT

Cancer cells have higher reactive oxygen species (ROS) than normal cells, due to genetic and metabolic alterations. An emerging scenario is that cancer cells increase ROS to activate protumorigenic signaling while activating antioxidant pathways to maintain redox homeostasis. Here we show that, in basal-like and BRCA1-related breast cancer (BC), ROS levels correlate with the expression and activity of the transcription factor aryl hydrocarbon receptor (AhR). Mechanistically, ROS triggers AhR nuclear accumulation and activation to promote the transcription of both antioxidant enzymes and the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). In a mouse model of BRCA1-related BC, cancer-associated AhR and AREG control tumor growth and production of chemokines to attract monocytes and activate proangiogenic function of macrophages in the tumor microenvironment. Interestingly, the expression of these chemokines as well as infiltration of monocyte-lineage cells (monocyte and macrophages) positively correlated with ROS levels in basal-like BC. These data support the existence of a coordinated link between cancer-intrinsic ROS regulation and the features of tumor microenvironment. Therapeutically, chemical inhibition of AhR activity sensitizes human BC models to Erlotinib, a selective EGFR tyrosine kinase inhibitor, suggesting a promising combinatorial anticancer effect of AhR and EGFR pathway inhibition. Thus, AhR represents an attractive target to inhibit redox homeostasis and modulate the tumor promoting microenvironment of basal-like and BRCA1-associated BC.


Subject(s)
Amphiregulin/genetics , BRCA1 Protein/genetics , Breast Neoplasms/genetics , Receptors, Aryl Hydrocarbon/genetics , Adult , Animals , Apoptosis/drug effects , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Female , Gene Expression Regulation, Neoplastic , Homeostasis/genetics , Humans , Mice , Middle Aged , Oxidation-Reduction/drug effects , Reactive Oxygen Species/metabolism , Tumor Microenvironment/genetics
10.
J Thorac Oncol ; 14(4): 656-671, 2019 04.
Article in English | MEDLINE | ID: mdl-30578931

ABSTRACT

INTRODUCTION: Targeted therapies for lung adenocarcinoma (LUAD) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination-based therapies that target both mutated oncogenes and key modifiers of oncogene-driven tumorigenesis. This is based on the premise that mutated oncogenes, although necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LUAD development. METHODS: We performed integrative genomic analyses, combining copy number, gene expression and mutational information for over 500 LUAD tumors. Co-immunoprecipitation and Western blot analysis were performed in LUAD cell lines to confirm candidate interactions while RNA interference and gene overexpression were used for in vitro and in vivo functional assessment. RESULTS: We identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of dual specificity phosphatase 4 (DUSP4), which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant-EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. We found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LUAD. CONCLUSIONS: These data suggest that overexpression of GGA2 in LUAD tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LUAD development and is a potential therapeutic target for combination-based strategies in LUAD.


Subject(s)
Adaptor Proteins, Vesicular Transport/genetics , Lung Neoplasms/genetics , 3T3 Cells , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Carcinogenesis , Cell Line, Tumor , Chromosome Deletion , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Amplification , Genomics , HEK293 Cells , HeLa Cells , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Mutation , Signal Transduction
12.
Sci Rep ; 8(1): 16562, 2018 11 08.
Article in English | MEDLINE | ID: mdl-30410118

ABSTRACT

Previous research has suggested that thyroid hormone receptor alpha 1 (THRα1), a hormone responsive splice variant, may play a role in breast cancer progression. Whether THRα1 can be exploited for anti-cancer therapy is unknown. The antiproliferative and antitumor effects of dronedarone, an FDA-approved anti-arrhythmic drug which has been shown to antagonize THRα1, was evaluated in breast cancer cell lines in vitro and in vivo. The THRα1 splice variant and the entire receptor, THRα, were also independently targeted using siRNA to determine the effect of target knockdown in vitro. In our study, dronedarone demonstrates cytotoxic effects in vitro and in vivo in breast cancer cell lines at doses and concentrations that may be clinically relevant. However, knockdown of either THRα1 or THRα did not cause substantial anti-proliferative or cytotoxic effects in vitro, nor did it alter the sensitivity to dronedarone. Thus, we conclude that dronedarone's cytotoxic effect in breast cancer cell lines are independent of THRα or THRα1 antagonism. Further, the depletion of THRα or THRα1 does not affect cell viability or proliferation. Characterizing the mechanism of dronedarone's anti-tumor action may facilitate drug repurposing or the development of new anti-cancer agents.


Subject(s)
Antineoplastic Agents/administration & dosage , Breast Neoplasms/drug therapy , Dronedarone/administration & dosage , Thyroid Hormone Receptors alpha/genetics , Animals , Antineoplastic Agents/pharmacology , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dronedarone/pharmacology , Drug Repositioning , Female , Humans , Mice , RNA, Small Interfering/pharmacology , Thyroid Hormone Receptors alpha/antagonists & inhibitors , Xenograft Model Antitumor Assays
13.
Proc Natl Acad Sci U S A ; 115(8): 1913-1918, 2018 02 20.
Article in English | MEDLINE | ID: mdl-29434041

ABSTRACT

Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated KRAS or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment. Centrosome numbers and mitotic spindles were scored. CFI-400945 treatment produced supernumerary centrosomes and mitotic defects in lung cancer cells. In vivo antineoplastic activity of CFI-400945 was established in mice with syngeneic lung cancer xenografts. Lung tumor growth was significantly inhibited at well-tolerated dosages. Phosphohistone H3 staining of resected lung cancers following CFI-400945 treatment confirmed the presence of aberrant mitosis. PLK4 expression profiles in human lung cancers were explored using The Cancer Genome Atlas (TCGA) and RNA in situ hybridization (RNA ISH) of microarrays containing normal and malignant lung tissues. PLK4 expression was significantly higher in the malignant versus normal lung and conferred an unfavorable survival (P < 0.05). Intriguingly, cyclin dependent kinase 2 (CDK2) antagonism cooperated with PLK4 inhibition. Taken together, PLK4 inhibition alone or as part of a combination regimen is a promising way to combat lung cancer.


Subject(s)
Apoptosis/drug effects , Indazoles/pharmacology , Indoles/pharmacology , Polyploidy , Protein Serine-Threonine Kinases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Centrosome , Gene Expression Regulation, Neoplastic , Humans , Indazoles/therapeutic use , Indoles/therapeutic use , Mice , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism
14.
Nat Commun ; 9(1): 166, 2018 01 09.
Article in English | MEDLINE | ID: mdl-29317617

ABSTRACT

In the original version of this Article, financial support was not fully acknowledged. This error has now been corrected in both the PDF and HTML versions of the Article.

15.
Nat Commun ; 8(1): 1126, 2017 10 24.
Article in English | MEDLINE | ID: mdl-29066719

ABSTRACT

Next-generation sequencing technologies have recently been used in pharmacogenomic studies to characterize large panels of cancer cell lines at the genomic and transcriptomic levels. Among these technologies, RNA-sequencing enable profiling of alternatively spliced transcripts. Given the high frequency of mRNA splicing in cancers, linking this feature to drug response will open new avenues of research in biomarker discovery. To identify robust transcriptomic biomarkers for drug response across studies, we develop a meta-analytical framework combining the pharmacological data from two large-scale drug screening datasets. We use an independent pan-cancer pharmacogenomic dataset to test the robustness of our candidate biomarkers across multiple cancer types. We further analyze two independent breast cancer datasets and find that specific isoforms of IGF2BP2, NECTIN4, ITGB6, and KLHDC9 are significantly associated with AZD6244, lapatinib, erlotinib, and paclitaxel, respectively. Our results support isoform expressions as a rich resource for biomarkers predictive of drug response.


Subject(s)
Biomarkers/metabolism , Drug Screening Assays, Antitumor , Neoplasms/drug therapy , Neoplasms/genetics , Pharmacogenetics , Protein Isoforms/genetics , Alternative Splicing , Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Breast Neoplasms/genetics , Carrier Proteins/genetics , Cell Adhesion Molecules/genetics , Chemistry, Pharmaceutical , Erlotinib Hydrochloride/pharmacology , Genome, Human , Humans , Integrin beta Chains/genetics , Lapatinib , Paclitaxel/pharmacology , Quinazolines/pharmacology , RNA, Messenger/metabolism , RNA-Binding Proteins/genetics , Sequence Analysis, RNA , Transcriptome
16.
Oncotarget ; 8(31): 50489-50499, 2017 Aug 01.
Article in English | MEDLINE | ID: mdl-28881577

ABSTRACT

Recent literature suggests that most widely used ovarian cancer (OVCA) cell models do not recapitulate the molecular features of clinical tumors. To address this limitation, we generated 18 cell lines and 3 corresponding patient-derived xenografts predominantly from high-grade serous carcinoma (HGSOC) peritoneal effusions. Comprehensive genomic characterization and comparison of each model to its parental tumor demonstrated a high degree of molecular similarity. Our characterization included whole exome-sequencing and copy number profiling for cell lines, xenografts, and matched non-malignant tissues, and DNA methylation, gene expression, and spectral karyotyping for a subset of specimens. Compared to the Cancer Genome Atlas (TCGA), our models more closely resembled HGSOC than any other tumor type, justifying their validity as OVCA models. Our meticulously characterized models provide a crucial resource for the OVCA research community that will advance translational findings and ultimately lead to clinical applications.

17.
Nat Commun ; 8: 14432, 2017 02 17.
Article in English | MEDLINE | ID: mdl-28211448

ABSTRACT

G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).


Subject(s)
BRCA1 Protein/deficiency , BRCA2 Protein/deficiency , Benzothiazoles/pharmacology , Benzothiazoles/therapeutic use , G-Quadruplexes , Naphthyridines/pharmacology , Naphthyridines/therapeutic use , Neoplasms/drug therapy , Animals , Base Sequence , Benzoxazines/pharmacology , Caenorhabditis elegans/drug effects , Cell Line, Tumor , Chromosomal Instability/genetics , DNA Damage , DNA Repair/drug effects , DNA Replication/drug effects , DNA, Ribosomal/genetics , Female , G-Quadruplexes/drug effects , Genome, Human , Genotype , Homologous Recombination/drug effects , Humans , Mice , Quinolones/pharmacology , Saccharomyces cerevisiae/metabolism , Transcription, Genetic/drug effects , Xenograft Model Antitumor Assays
18.
Proc Natl Acad Sci U S A ; 114(7): E1148-E1157, 2017 02 14.
Article in English | MEDLINE | ID: mdl-28137882

ABSTRACT

Wnt signaling, named after the secreted proteins that bind to cell surface receptors to activate the pathway, plays critical roles both in embryonic development and the maintenance of homeostasis in many adult tissues. Two particularly important cellular programs orchestrated by Wnt signaling are proliferation and stem cell self-renewal. Constitutive activation of the Wnt pathway resulting from mutation or improper modulation of pathway components contributes to cancer development in various tissues. Colon cancers frequently bear inactivating mutations of the adenomatous polyposis coli (APC) gene, whose product is an important component of the destruction complex that regulates ß-catenin levels. Stabilization and nuclear localization of ß-catenin result in the expression of a panel of Wnt target genes. We previously showed that Mule/Huwe1/Arf-BP1 (Mule) controls murine intestinal stem and progenitor cell proliferation by modulating the Wnt pathway via c-Myc. Here we extend our investigation of Mule's influence on oncogenesis by showing that Mule interacts directly with ß-catenin and targets it for degradation under conditions of hyperactive Wnt signaling. Our findings suggest that Mule uses various mechanisms to fine-tune the Wnt pathway and provides multiple safeguards against tumorigenesis.


Subject(s)
Tumor Suppressor Proteins/physiology , Ubiquitin-Protein Ligases/physiology , Wnt Signaling Pathway , beta Catenin/antagonists & inhibitors , Adenomatous Polyposis Coli Protein/deficiency , Animals , Axin Protein/biosynthesis , Axin Protein/genetics , Cell Nucleus/metabolism , Cell Nucleus/ultrastructure , Colonic Neoplasms/metabolism , Cyclin D1/biosynthesis , Cyclin D1/genetics , Down-Regulation , Genes, APC , Genes, Tumor Suppressor , HEK293 Cells , Humans , Mice , Mice, Knockout , Neoplasm Proteins/physiology , Organoids/metabolism , Organoids/ultrastructure , Protein Binding , Protein Processing, Post-Translational , Proteolysis , RNA Interference , RNA, Small Interfering/genetics , Recombinant Proteins/metabolism , Tumor Suppressor Proteins/antagonists & inhibitors , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/genetics , Ubiquitin-Protein Ligases/antagonists & inhibitors , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics , Ubiquitination
19.
Nat Genet ; 48(10): 1260-6, 2016 10.
Article in English | MEDLINE | ID: mdl-27571262

ABSTRACT

Sustained expression of the estrogen receptor-α (ESR1) drives two-thirds of breast cancer and defines the ESR1-positive subtype. ESR1 engages enhancers upon estrogen stimulation to establish an oncogenic expression program. Somatic copy number alterations involving the ESR1 gene occur in approximately 1% of ESR1-positive breast cancers, suggesting that other mechanisms underlie the persistent expression of ESR1. We report significant enrichment of somatic mutations within the set of regulatory elements (SRE) regulating ESR1 in 7% of ESR1-positive breast cancers. These mutations regulate ESR1 expression by modulating transcription factor binding to the DNA. The SRE includes a recurrently mutated enhancer whose activity is also affected by rs9383590, a functional inherited single-nucleotide variant (SNV) that accounts for several breast cancer risk-associated loci. Our work highlights the importance of considering the combinatorial activity of regulatory elements as a single unit to delineate the impact of noncoding genetic alterations on single genes in cancer.


Subject(s)
Breast Neoplasms/genetics , Estrogen Receptor alpha/genetics , Mutation , Polymorphism, Single Nucleotide , CRISPR-Cas Systems , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , MCF-7 Cells , Regulatory Sequences, Nucleic Acid , Transcription Factors/metabolism
20.
Cancer Cell ; 30(2): 337-348, 2016 08 08.
Article in English | MEDLINE | ID: mdl-27424808

ABSTRACT

Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/genetics , DNA Damage , DNA Repair , DNA-Binding Proteins/genetics , Hematopoietic Stem Cells/enzymology , Isocitrate Dehydrogenase/genetics , Proto-Oncogene Proteins/genetics , Animals , Ataxia Telangiectasia Mutated Proteins/metabolism , DNA-Binding Proteins/metabolism , Dioxygenases , Down-Regulation , Hematopoietic Stem Cells/cytology , Humans , Isocitrate Dehydrogenase/metabolism , Mice , Mutation , Proto-Oncogene Proteins/metabolism
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