PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors
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AbstractWe aimed to develop novel drug combination strategy to overcome drug resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in the treatment of lung cancer. EGFR TKIs are approved for treating advanced lung cancer that harbors the sensitizing EGFR mutations. However, resistance to EGFR TKIs is almost inevitable for all patients due to multifactorial mechanisms. The PI3K/Akt/mTOR pathway is a major signaling pathway regulated by EGFR to drive cancer survival. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor, which upon activation upregulates PTEN to inhibit cell signaling downstream of PI3K to mediate apoptosis. To this end, PTEN loss is a known mechanism contributing to intrinsic resistance to EGFR TKIs. Therefore, PPARγ agonists are hypothesized to overcome EGFR TKI resistance. Using well defined human non-small cell lung cancer (NSCLC) cell model with PTEN deficiency, the potentiation of EGFR TKI anticancer activity by PPARγ agonists was demonstrated. PPARγ agonists were found to upregulate PTEN, subsequently inhibit the PI3K-Akt signaling pathway, and thus enhancing the anticancer activity of gefitinib (a first generation EGFR TKI). Specific PPARγ inhibitor (GW9662) and genetic silencing of PPARγ were shown to prevent this potentiation of anticancer activity by PPARγ agonists, thus confirming the crucial role played by PPARγ activation. Interestingly, the tested PPARγ 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. PPARγ 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 by the PPARγ agonists.
Our findings thus provide the basis for the rational and personalized use of PPARγ agonists in combination with EGFR TKIs in lung cancer patients with specific resistance mechanism.
Acceptance Date01/02/2017
All Author(s) ListTo KK, Tong WS, Wu WK, Loong HH
Name of ConferenceAmerican Association for Cancer Research Annual Meeting 2017
Start Date of Conference01/04/2017
End Date of Conference05/04/2017
Place of ConferenceWashington D.C., U.S.A.
Country/Region of ConferenceUnited States of America
LanguagesEnglish-United States
KeywordsEGFR tyrosine kinase inhibitor, PTEN, drug resistance, PPARgamma

Last updated on 2018-22-01 at 05:54