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Principal Investigator: Andrea Christine Chaikovsky
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $101,390
Funding agency: National Cancer Institute
PROJECT SUMMARY
As tumors progress, cancer cells acquire characteristics that allow them to adapt to various stresses. In fact,
one of the best predictors of patient outcome is disease stage at the time of diagnosis, as advanced tumors are
more aggressive and difficult to treat. However, the underlying mechanisms that potentiate increased cell
plasticity throughout cancer progression remain poorly understood. The ability of cancer cells to adapt has
posed a particular problem for the use of targeted therapies, which are frequently rendered ineffective by the
emergence of acquired resistance. The goal of this work is to elucidate molecular mechanisms that regulate
the cell cycle and cell fate decisions to influence cancer progression and resistance to targeted therapy. In the
F99 phase, I aim to identify novel factors that regulate the retinoblastoma (RB) pathway and influence the
cellular response to inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6). CDK4/6, in complex with Cyclin
D, phosphorylate and inactivate the tumor suppressor RB to drive cell cycle progression. Recently developed
CDK4/6 inhibitors have shown some promise in the clinic, but every patient given these inhibitors eventually
progresses, creating an urgent need to identify mechanisms of resistance. Using an in vitro genome-wide
CRISPR/Cas9 screen, I recently identified loss of the E3 ligase adaptor AMBRA1 as a potential mechanism of
resistance to CDK4/6 inhibition. Further, AMBRA1 loss increased Cyclin D protein stability. I hypothesize that
AMBRA1, with its accompanying E3 ligase complex, targets Cyclin D for degradation, and that AMBRA1 loss
could be a mechanism of resistance to CDK4/6 inhibitors in vivo. I will use molecular and biochemical assays
to identify the E3 ligase that cooperates with AMBRA1 to target Cyclin D. In addition, I will combine tumor
barcoding with multiplexed CRISPR/Cas9-mediated gene targeting in mouse models of non-small cell lung
cancer to determine whether loss of AMBRA1 leads to CDK4/6 inhibitor resistance in vivo. In the K00 phase, I
aim to elucidate the molecular mechanisms regulating cell identity in lung adenocarcinoma (LUAD). Treatment
of LUAD with small molecule inhibitors targeting mutant receptor tyrosine kinases can lead to relapsed tumors
that have transdifferentiated into small cell lung cancer, an aggressive neuroendocrine cancer with limited
treatment options. However, the mechanism of transdifferentiation is largely unknown. I propose to develop cell
line and mouse models of this transdifferentiation process in order to identify factors that regulate LUAD cell
identity and ultimately identify means to prevent or reverse transdifferentiation. Together, this body of work will
elucidate fundamental principles of acquired resistance and disease progression in lung cancer, which may
also be applicable to other cancer types.
Terms: <Active Follow-up><Adenocarcinoma Cell><Assay><Bar Codes><Bio-Informatics><Bioassay><Biochemical><Bioinformatics><Biological Assay><CCND1 Protein><CDK Inhibitor Protein><CDK4><CDK4 gene><CDKI Protein><CRISPR approach><CRISPR based approach><CRISPR editing screen><CRISPR method><CRISPR methodology><CRISPR screen><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based screen><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 screen><CRISPR/Cas9 technology><Cancer Cause><Cancer Etiology><Cancer cell line><Cancers><Cas nuclease technology><Cell Body><Cell Cycle><Cell Cycle Progression><Cell Division Cycle><Cell Division Kinase 4><Cell Line><CellLine><Cells><Cessation of life><Characteristics><Clinic><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Cyclin D1><Cyclin Gene><Cyclin Kinase Inhibitor><Cyclin-Dependent Kinase 4><Cyclin-Dependent Kinase Inhibitor><Cyclins><Death><Diagnosis><Disease><Disease Progression><Disorder><Drug resistance><E3 Ligase><E3 Ubiquitin Ligase><G1/S Transition><G1/S-Specific Cyclin D1><GEM model><GEMM model><Gene Targeting><Genes><Genetic study><Genetically Engineered Mouse><Global Change><Goals><In Vitro><Investigators><Kinases><Ligase><Ligase Gene><Lung Adenocarcinoma><Malignant><Malignant - descriptor><Malignant Cell><Malignant Glandular Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Molecular><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neuroendocrine><Neuroendocrine System><Neurosecretory Systems><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oat cell carcinoma><Oncogenesis><Oncogenic><PRAD1 Protein><PSK-J3><PTK Inhibitors><PTK Receptors><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phase><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Postdoc><Postdoctoral Fellow><Process><Protein Phosphorylation><Protein Tyrosine Kinase Inhibitors><Proteins><Proto-Oncogene Proteins c-bcl-1><Pulmonary Cancer><Pulmonary malignant Neoplasm><R-Series Research Projects><R01 Mechanism><R01 Program><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Relapse><Research><Research Associate><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Resistance><Retinal Neuroblastoma><Retinoblastoma><Role><Route><Signal Pathway><Small Cell Lung Cancer><Strains Cell Lines><Stress><Structure><Synthetases><TK Inhibitors><Testing><Time><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tumor Suppressor Proteins><Tyrosine Kinase Inhibitor><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Ubiquitilation><Ubiquitin Protein Ligase><Ubiquitin-Protein Ligase Complexes><Ubiquitin-Protein Ligase E3><Ubiquitination><Ubiquitinoylation><Work><active followup><barcode><bcl-1 Proto-Oncogene Products><bcl-1 Proto-Oncogene Proteins><bcl1 Proto-Oncogene Proteins><c-bcl-1 Proteins><cancer cell><cancer progression><cancer sub-types><cancer subtypes><cancer type><career><clustered regularly interspaced short palindromic repeats screen><cultured cell line><cyclin D><driver lesion><driver mutation><drug resistant><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><genetically engineered mouse model><genetically engineered murine model><genome scale><genome-wide><genomewide><improved><in vivo><in vivo Model><inhibitor><insight><lung cancer><lung cancer cell><lung oat cell carcinoma><lung small cell neuroendocrine carcinoma><malignancy><mouse model><murine model><mutant><neoplasm progression><neoplasm/cancer><neoplastic progression><neuroendocrine cancer><neuroendocrine malignancy><novel><oat cell cancer><pathway><patient oriented outcomes><post-doc><post-doctoral><post-doctoral trainee><prevent><preventing><receptor><research associates><resistance mechanism><resistance to Drug><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to therapy><response><restraint><retina neuroblastoma><retinoblastoma pathway><retinoblastoma tumor suppressor><small cell lung carcinoma><small cell undifferentiated carcinoma><small molecular inhibitor><small molecule><small molecule inhibitor><social role><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapy resistant><transdifferentiation><treatment resistance><tumor><tumor progression><tumor suppressor><tumorigenesis><ubiquination><ubiquitin conjugation><ubiquitin-protein ligase>