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Principal Investigator: Jixin Dong
Organization: UNIVERSITY OF NEBRASKA MEDICAL CENTER
Fiscal Year: 2024
Award: $556,553
Funding agency: National Cancer Institute
Abstract Text
Many antitubulin agents, such as paclitaxel (Taxol), have been used extensively for treatment of
several types of cancer, including ovarian, lung, pancreatic, and breast cancers. Despite their
wide use in cancer treatment, however, patient response is highly variable and drug resistance
remains a major clinical issue. It is therefore essential to identify prognostic markers to predict the
patient response and to enhance drug sensitivity. Protein kinase R (PKR) plays significant roles
in innate immune response to viral infection and tumorigenesis. The biological significance of PKR
in antitubulin chemotherapeutics and underlying mechanisms have yet to be defined. Through
Phos-tag-based kinome-wide biochemical screens, we identified PKR as a critical regulator in
antitubulin cytotoxicity. Our preliminary data suggest that inactivation of PKR confers resistance
to Taxol in ovarian and breast cancer cells. Enhanced expression of PKR potentiates taxol
cytotoxicity in vitro and in vivo. We further identified novel phosphorylation sites on PKR during
antitubulin-mitotic arrest and in normal mitosis. Mechanistically, our findings also suggest that
PKR controls Taxol chemosensitivity through modulating Bcl2 expression. Our hypothesis is that
the PKR-Bcl2 axis functions as a therapeutic target for antitubulin agent-based
chemotherapeutics in treatment of drug-resistant and/or recurrent patients. We will test our central
hypothesis by three specific aims. Aim 1: Examine the functional significance of PKR in antitubulin
chemotherapeutics in vivo; Aim 2: Determine how antitubulin drugs regulate PKR; Aim 3:
Elucidate the mechanisms and downstream signaling of PKR in antitubulin chemosensitivity. The
identification of new regulators and/or signaling pathways triggered by antitubulin drugs will shed
light on the mechanisms underlying chemoresistance. Our study suggests that combining kinase
activators (e.g., being characterized in this application) for PKR or Bcl2 inhibitors (FDA-approved)
with antitubulin agents will have enhanced efficacy in treatment of drug-resistant and/or recurrent
patients. Our findings also suggest that profiling PKR-Bcl2 signaling status of tumors
(mRNA/protein levels and activity) can be useful to predict the patient response to antitubulin
chemotherapeutics.
Terms: <ATP-protein phosphotransferase><Affect><Agonist><Animal Model><Animal Models and Related Studies><Anzatax><Apoptotic><Asotax><B cell lymphoma 2><B-Cell CLL/Lymphoma 2 Gene><B-cell lymphoma/leukemia-2><BCL2><BCL2 gene><Bcl-2><Biochemical><Biological><Biological Markers><Breast Cancer><Breast Cancer Cell><Bristaxol><Cancer Cell Growth><Cancer Patient><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Death><Cell Death Induction><Cell Signaling><Cells><Cellular Metabolic Process><Cellular Stress><Cellular Stress Response><Chemoresistance><Clinic><Clinical><Clinical Trials><DNA Damage><DNA Injury><Data><Double-Stranded RNA><Drug Therapy><Drug resistance><Drugs><Eukaryotic Initiation Factors><Eukaryotic Peptide Initiation Factors><Eukaryotic Translation Initiation Factors><FDA approved><Family><Human><IF2 Protein><IFN><Immune response><Immunocompetent><Immunological response><In Vitro><Initiation Factor-2><Innate Immune Response><Interferons><Intermediary Metabolism><Intracellular Communication and Signaling><Kinase Family Gene><Kinases><Knowledge><Lytotoxicity><M Phase><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant neoplasm of lung><Malignant neoplasm of ovary><Malignant neoplasm of pancreas><Mediating><Medication><Messenger RNA><Metabolic Processes><Metabolism><Micro-tubule><Microtubules><Mitosis><Mitosis Stage><Mitotic><Modern Man><Molecular><Molecular Target><Multi-Drug Resistance><Multidrug Resistance><Multiple Drug Resistance><Multiple Drug Resistant><Oncogenesis><Outcome><Ovary Cancer><Paclitaxel><Paclitaxel (Taxol)><Pancreas Cancer><Pancreatic Cancer><Pathway interactions><Patients><Peptide Initiation Factor 2><Peptide Initiation Factor IF-2><Pharmaceutical Preparations><Pharmacotherapy><Phosphorylation><Phosphorylation Site><Phosphotransferase Gene><Phosphotransferases><Play><Praxel><Prognostic Marker><Prokaryotic Initiation Factor-2><Protein Kinase><Protein Phosphorylation><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><Recurrence><Recurrent><Regulation><Resistance><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Stress><Taxol><Taxol A><Taxol Konzentrat><Testing><Text><Therapeutic><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Translating><Translational Initiation Factor 2><Transphosphorylases><Tubulin><Validation><Viral Diseases><Virus Diseases><anti-cancer therapy><anti-tumor agent><bcl-2 Genes><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><breast tumor cell><cancer cell><cancer therapy><cancer type><cancer-directed therapy><ced9 homolog><cell metabolism><cell stress><cellular metabaolism><chemoresistant><chemotherapy resistance><chemotherapy resistant><cytokine><cytotoxicity><drug resistant><drug sensitivity><drug treatment><drug/agent><dsRNA><glycogen synthase a kinase><host response><hydroxyalkyl protein kinase><immune competent><immune system response><immunoresponse><improved><in vivo><infB Gene Product><infB Protein><inhibitor><lung cancer><mRNA><malignancy><malignant breast tumor><model of animal><multi-drug resistant><multidrug resistant><necrocytosis><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ovarian cancer><pancreatic malignancy><pathway><patient response><patient specific response><pharmacologic><phosphorylase b kinase kinase><pre-clinical><preclinical><prognostic biomarker><protein expression><protein function><protein kinase R><protein profiling><resistance to Drug><resistant><resistant to Drug><response><responsive patient><social role><therapeutic target><tumor><tumorigenesis><validations><viral infection><virus infection><virus-induced disease>