Wednesday, May 8, 2024
5/8/2024
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.
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