A5031716277- Advanced Breast Cancer Therapies
- Cancer-related Molecular Pathways
- Pancreatic and Hepatic Oncology Research
- Peptidase Inhibition and Analysis
- Microtubule and mitosis dynamics
- Protease and Inhibitor Mechanisms
- Cancer Research and Treatments
- Cancer Genomics and Diagnostics
- Thyroid Cancer Diagnosis and Treatment
- DNA and Nucleic Acid Chemistry
- DNA Repair Mechanisms
- Genomics and Chromatin Dynamics
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Lung Cancer Research Studies
- Cancer Mechanisms and Therapy
- Immune cells in cancer
- Single-cell and spatial transcriptomics
- Machine Learning in Bioinformatics
- Synthesis and Biological Evaluation
- Advanced biosensing and bioanalysis techniques
- Plant Genetic and Mutation Studies
- Chronic Lymphocytic Leukemia Research
- Wnt/β-catenin signaling in development and cancer
- RNA and protein synthesis mechanisms
Roswell Park Comprehensive Cancer Center
2019-2025
University of Arizona
2014-2023
Cancer Genetics (United States)
2022-2023
The p27 protein is a canonical negative regulator of cell proliferation and acts primarily by inhibiting cyclin-dependent kinases (CDKs). Under some circumstances, associated with active CDK4, but no mechanism for activation has been described. We found that p27, when phosphorylated tyrosine kinases, allosterically activated CDK4 in complex cyclin D1 (CDK4-CycD1). Structural biochemical data revealed binding (phosp27) to altered the kinase adenosine triphosphate site promote phosphorylation...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that lacks effective treatment options, highlighting the need for developing new therapeutic interventions. Here, we assessed response to pharmacologic inhibition of KRAS, central oncogenic driver PDAC. In a panel PDAC cell lines, KRASG12D with MRTX1133 yielded variable efficacy in suppressing growth and downstream gene expression programs 2D cultures. On basis CRISPR-Cas9 loss-of-function screens, ITGB1 was identified...
Abstract CDK2 inhibitors have recently been developed and entered clinical trials. Combination approaches can help broaden the use of therapeutic agents establish more effective treatments. Here, we evaluated selective inhibitor BLU-222 for mechanisms response in context ovarian breast cancer models. Sensors cellular CDK activity indicated that sensitivity to either CDK4/6 or inhibition was related differential dependence on a single G1/S transition. Unlike inhibitors, able robustly inhibit...
Objective This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means treat pancreatic cancer. Design Patient-derived cell lines xenograft models were used response CDK4/6 MEK in tumour compartment. Impacts relative immunotherapy performed using subcutaneous orthotopic syngeneic models. Single-cell RNA sequencing multispectral imaging employed delineate effects on immunological milieu microenvironment. Results We found that...
Intrinsic or acquired resistance to clinically approved CDK4/6 inhibitors has emerged as a major obstacle that hinders their utility beyond ER
Anti-estrogens or aromatase inhibitors in combination with cyclin-dependent kinase 4 and 6 (CDK4/6) are the current standard of care for estrogen receptor-positive (ER+) Her-2 negative metastatic breast cancer. Although these therapies prolong progression-free survival compared to endocrine therapy alone, growth-arrested state residual tumor cells is clearly transient. Tumor that escape what might be considered a dormant quiescent regain proliferative capacity often acquire resistance...
Abstract Cyclin dependent kinase 2 (CDK2) regulates cell cycle and is an emerging target for cancer therapy. There are relatively small numbers of tumor models that exhibit strong dependence on CDK2 undergo G1 arrest following inhibition. The expression P16INK4A cyclin E1 determines this sensitivity to co-expression these genes occurs in breast patients highlighting their clinical significance as predictive biomarkers CDK2-targeted therapies. In genetically independent CDK2, pharmacological...
<p>Differential vulnerabilities to CDK2 versus CDK4/6 inhibition. A, Table of top identified predictive genes in breast and ovarian carcinomas for response inhibition from the publicly available DepMap dataset using CRISPR (top) RNAi (bottom) screens. B, Cell Titer Glo values normalized 0 nM treatment cancer cells treated with BLU-222 5 days. C, summarizing cell line treatment. D, COV-504 PE-O1 lines serial concentrations or palbociclib days monitored Cellcyte Incucyte live...
<p>Supplemental Figure S1-7 Legends</p>
<p>Figure S6. P16INK4A is a key determinant of response to BLU-222. A, Heatmap analysis from the cancer dependency map (DepMap) database displaying relative expression <i>CCNE1</i> and several endogenous CDK inhibitor genes in panel established ovarian breast cell lines. B, Western blot RB1-E2F pathway activity MDA-MB-157 cells following overexpression (OE) <i>CDK4</i> with without BLU-222 treatment. C, Live proliferative monitoring WT (left) overexpressing (OE,...
<p>Figure S7. Prevalence of Cyclin E1-P16INK4A<sup>high</sup> tumors that express RB. A, Kaplan Meier curves based on <i>CCNE1</i> status generated from The Cancer Genome Atlas (TCGA) serous ovarian carcinoma database. HR, hazard ratio; DFS, disease-free survival; OS, overall survival. Amp, amplification. B, Oncoprint the TCGA database for indicated cell cycle genes. C, Normalized intensity D1, E1, or P16INK4A expression within clusters 1, 3, and 4 (n = 82002...
<div>Abstract<p>Cyclin-dependent kinase 2 (CDK2) inhibitors have recently been developed and entered clinical trials. Combination approaches can help broaden the use of therapeutic agents establish more effective treatments. Here, we evaluated selective CDK2 inhibitor BLU-222 for mechanisms response in context ovarian breast cancer models. Sensors cellular CDK activity indicated that sensitivity to either CDK4/6 or inhibition was related differential dependence on a single...
<p>Figure S5. Cooperative and antagonistic combination strategies with BLU-222. A, BLISS synergistic analysis for antagonism between BLU-222 CHK1 checkpoint kinase inhibitors in MDA-MB-231 cells (n = 3 per group; scores calculated SynergyFinder v3). B, Live cell proliferative monitoring of the indicated lines treated BLU-222, palbociclib, or 3–4 one-way ANOVA; error bars represent SEM). C, Quantification mVenus-DHB mCherry-RB CDK activity sensor localization to cytosol nucleus HCC-1806...
<p>Figure S3. BLU-222 elicits potent G1 arrest in Cyclin E1 and P16INK4A-high models expressing RB. A, Cell cycle profiling from univariate flow cytometric analysis the indicated cell lines following treatment with palbociclib. B, Bivariate transfection si<i>NT</i> or si<i>CCNE1</i> constructs. C, RNA sequencing gene set enrichment plots for E2F targets interferon alpha response pathways Kuramochi MDA-MB-157 cells 125 nM 100 nM, respectively, 48 hours compared...
<p>Figure S2. Contextual biochemical response to CDK inhibition. A, Western blot of RB1-E2F pathway activity in OVSAHO and MDA-MB-157 cells following BLU-222 or palbociclib treatment. B, Schematic depicting mVenus-DHB mCherry-RB reporter constructs. C, Representative images sensor OVCAR-3 T-47D treated with 500 nM (scale bar = 100 µm). D, Quantification localization the cytosol nucleus indicated ovarian breast cancer cell lines treatment either palbociclib. E, transfected...
<p>Figure S4. Loss of RB1 shifts phase arrest and sensitivity to BLU-222. A, Heatmap RNA sequencing data comparing differential gene expression between BLU-222-treated Kuramochi (125 nM BLU-222) OVCAR-8 (250 cells normalized respective DMSO-treated controls. B, Cell cycle profiling from univariate flow cytometric analysis at baseline, after 1 5 days treatment with 500 BLU-222, drug washout. C, Western blot for abrogation G2/M checkpoint signaling in following doxycycline (Dox)...
<p>Supplemental File 1. BLU-222 combinatorial drug screen data from MDA-MB-231 (tab 1) and COV-504 cells 2) reported in Figure 5. Data as percent growth compared to sole treatment with 0.1% DMSO.</p>
The gain-of-function mutation of the RET proto-oncogene, which encodes a receptor tyrosine kinase, is strongly associated with development several medullary thyroid carcinomas (MTCs). Thus, protein has been explored as an excellent target for progressive and advanced MTC. In this study we have demonstrated therapeutic strategy MTC by suppressing transcription proto-oncogene though stabilization G-quadruplex structure formed on promoter region gene using natural product berberine. Medullary...