Repurposing of clinically approved drugs as autophagy modulators to overcome drug resistance to molecular targeted tyrosine kinase inhibitors (TKI) in treating lung cancer
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AbstractIntroduction: The clinical efficacy of epidermal growth factor tyrosine kinase inhibitor (EGFR TKIs) in lung cancer patients carrying the sensitizing EGFR mutations is severely compromised by drug resistance. We aimed to develop novel drug combination by repurposing existing drugs not indicated for oncology to overcome drug resistance to EGFR TKIs.

Objectives:
(1) To investigate the role of autophagy in the therapeutic response of EGFR TKIs in a panel of NSCLCs with different sensitivities/drug resistance mechanisms
(2) To demonstrate and investigate the mechanism underlying the potentiation of anticancer activity of EGFR TKIs in NSCLC cells in vitro using the tested autophagy modulators
(3) To study the circumvention of EGFR TKI resistance in xenograft-bearing athymic nude mice by the most promising autophagy modulator identified

Methods: Drug combinations were evaluated by cell proliferation assay. Various standard techniques were employed to detect and evaluate the extent of autophagy and apoptosis, including fluorescence microscopy, flow cytometry, transmission electron microscopy, Western blot analysis and cell viability assays.

Results: Given the findings that autophagy induction contributed to the anticancer activity of EGFR TKIs in NSCLC, model autophagy inducers (Peroxisome proliferator-activated receptor gamma (PPARgamm agonists) were tested for resistance circumvention. PPARgamma also upregulates phosphatase and tensin homolog (PTEN) to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to resistance to EGFR TKIs. Using human NSCLC cell models with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARgamma agonists was evaluated. PPARgamma agonists were found to upregulate PTEN, subsequently inhibiting the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib. Chemical and genetic inhibition of PPARgamma were shown to prevent this potentiation of anticancer activity by PPARgamma agonists, thus confirming the crucial role played by PPARgamma activation. interestingly, the tested PPARgamma agonists were also found to induce autophagy, as evidenced by the increased expression of an autophagy marker LC3-II and the autophagic degradation of p62/SQSTM1. PPARgamma agonists-induced autophagic cell death was believed to contribute to the circumvention of resistance in PTEN-deficient cells because the genetic silencing of ATG5 (an autophagy mediator) was found to eliminate the drug potentiation effect. The drug combination was also shown to provide a slight but statistical significant potentiation of anticancer effect in tumor xenograft in mice.
All Author(s) ListTo KK, Loong, HH, Wu WK
Name of ConferenceHealth Research Symposium 2019 - Genomics and Big Data in Health and Disease
Start Date of Conference12/06/2019
End Date of Conference12/06/2019
Place of ConferenceHong Kong
Country/Region of ConferenceHong Kong
Year2019
Month6
Day12
Place of PublicationHong Kong
LanguagesEnglish-United States
KeywordsRepurposing, Autophagy, Drug resistance, Targeted drugs, Tyrosine kinase inhibitors, Lung cancer

Last updated on 2019-23-09 at 09:02