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Principal Investigator: Shi-Yong Sun
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $474,087
Funding agency: National Cancer Institute
SUMMARY
Epidermal growth factor receptor (EGFR)-targeted therapy with EGFR tyrosine kinase inhibitors (EGFR-TKIs),
particularly current third generation mutation-selective agents such as osimertinib (AZD9291 or TAGRISSOTM),
has achieved great success and provided significant clinical benefit in patients with EGFR activating mutations.
However, the development of unavoidable acquired resistance has become the major obstacle to patients
achieving long-term remission. Hence, there is an urgent unmet need in the clinic for the development of
effective strategies to overcome acquired resistance to EGFR-TKIs, particularly 3rd generation agents. The
peroxisome proliferator-activated receptor- (PPAR) coactivator-1 (PGC1) functions as a coactivator to
coordinate the activity of transcription factors such as PPAR to modulate energy metabolism, lipid
metabolisms and other cellular processes. Both PGC1 and PPAR have been implicated in promoting
tumorigenesis and mediating chemoresistance. Our RNA-seq analysis revealed that the expression of both
PPARGC1B (that encodes PGC1) and PPARG (that encodes PPAR) genes were significantly decreased in
osimertinib-treated EGFR mutant NSCLC cells; these findings were confirmed at the protein level as well.
Moreover, osimertinib-resistant cells possessed elevated levels of PGC1 and PPAR, which were resistant to
modulation by osimertinib. Importantly, inhibition of both PGC1 with knockdown and PPAR with knockdown
or different chemical antagonists restored the sensitivities of osimertinib-resistant cell lines to osimertinib.
These data suggest a critical role of the PGC1/PPAR axis in mediating therapeutic efficacy of osimertinib in
EGFR mutant NSCLC cells. Thus, we hypothesize that effective inhibition of the PGC1/PPAR axis is a
critical and essential event in maintaining long-term therapeutic efficacy of osimertinib or other 3rd generation
EGFR-TKIs in the treatment of EGFR mutant NSCLCs. This hypothesis will be tested by accomplishing the
following specific aims: 1) To demonstrate the biological significance of PGC1/PPAR modulation in
regulating the responses of EGFR mutant NSCLC cells to osimertinib including the development of acquired
resistance; 2) To elucidate the molecular mechanisms accounting for downregulation of PGC1 and PPAR by
osimertinib in EGFR mutant NSCLC cells; and 3) To develop efficacious strategies for overcoming acquired
resistance to osimertinib by targeting PPAR. The objectives of this proposal are to fully demonstrate the
mechanisms by which osimertinib negatively regulates PPARGC1B expression in EGFR mutant NSCLC cells,
to reveal the crucial role of PGC1/PPAR in mediating response of EGFR mutant NSCLC cells to 3rd
generation EGFR-TKIs including the development of acquired resistance, and to develop effective therapeutic
strategies to delay or overcome osimertinib acquired resistance by targeting this axis. This proposal will allow
us to gain new knowledge and deep understanding of the biology of 3rd generation EGFR-TKIs, and to develop
innovative therapeutic strategies for managing acquired resistance to 3rd generation EGFR-TKIs.
Terms: <Accounting><Affect><Agreement><Area><Basal Transcription Factor><Basal transcription factor genes><Biological><Biology><Cancer cell line><Cancers><Cell Body><Cell Function><Cell Line><Cell Physiology><Cell Process><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemicals><Chemoresistance><Clinic><Clinical><Data><Development><Disease><Disease remission><Disorder><Down-Regulation><EGF Receptor><EGFR><EGFR Blocker><EGFR Inhibitor><EGFR Tyrosine Kinase Inhibitor><EGFR-TK Inhibitor><ERBB Protein><Ectopic Expression><Energy Expenditure><Energy Metabolism><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Inhibitor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor><Epidermal Growth Factor-Urogastrone Receptors><Event><FDA approved><FOSL1><FOSL1 gene><FRA1><Fos-Like Antigen 1 Gene><Gene Family><General Transcription Factor Gene><General Transcription Factors><Generations><Genes><Genetic Alteration><Genetic Change><Genetic Suppression><Genetic defect><HER1><HUMPPARG><In Vitro><Knowledge><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Molecular><Mutation><NR1C3><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oncogenesis><PPAR><PPAR gamma><PPAR-g><PPAR-γ><PPARG><PPARG gene><PPARG1><PPARG2><PPARgamma><PPARγ><Patients><Peroxisome Proliferative Activated Receptor Gamma><Peroxisome Proliferator-Activated Receptor gamma><Peroxisome Proliferator-Activated Receptor γ><Peroxisome Proliferator-Activated Receptors><Play><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><RNA Seq><RNA sequencing><RNAseq><Regulation><Remission><Resistance><Resistance development><Resistant development><Role><Strains Cell Lines><Subcellular Process><TGF-alpha Receptor><Testing><Therapeutic><Thiazolidinedione Receptor><Transcription Factor Proto-Oncogene><Transcription factor genes><Transforming Growth Factor alpha Receptor><Treatment Efficacy><Urogastrone Receptor><adipogenesis><antagonism><antagonist><biologic><c-erbB-1><c-erbB-1 Protein><chemoresistant><chemotherapy resistance><chemotherapy resistant><cultured cell line><developing resistance><developmental><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><fat metabolism><genetic approach><genetic strategy><genome mutation><improved><in vivo><in vivo Model><innovate><innovation><innovative><intervention efficacy><knock-down><knockdown><lipid biosynthesis><lipid metabolism><lipogenesis><lung cancer><lung cancer cell><malignancy><mutant><neoplasm/cancer><overexpress><overexpression><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><promoter><promotor><proto-oncogene protein c-erbB-1><resistance mutation><resistant><resistant mutation><response><social role><success><targeted cancer therapy><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapeutically effective><therapy efficacy><transcription factor><transcriptome sequencing><transcriptomic sequencing><tumorigenesis>