Abstract 2924: Suppressing SET reactivates PP2A function in EGFR wide-type NSCLC and synergizes with taxol to exert anti-cancer effects
Authors: Man-Hsin Hung, Chung-Wai Shiau, Yung-Jen Hsiao, Hui-Chuan Yu, Wei-Tien Tai, Chun-Yu Liu, Cheng-Yi Wang, Kuen-Feng Chen
Journal: Cancer Research (2015)

Abstract Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated death in the world. Conventional chemotherapy is the standard-of-care for majority of patients with advance NSCLC and tyrosine kinase inhibitors of epithelial growth factor receptor (EGFR) only benefit patients with tumor containing specific mutation forms of EGFR. However, high disease recurrence rate after currently available therapeutics limited patient's survival. Therefore, there is a timely need to improve current treatment for patients with NSCLC, especially those with EGFR wide type tumors. Protein phosphatase 2A (PP2A) is an important tumor suppression whose function is inhibited in tumor tissue by the appearance of SET. In current study, we showed that inhibiting SET binding to PP2A by a novel small molecular compound significantly improved the chemosensitivity of EGFR wide-type NSCLC cells. Method: EGFR wide-type NSCLC cell lines, including A549, H358 and H460, were treated with taxol and a novel quinzoline derivative, PA, which was designed and developed to interrupt the binding of SET to PP2A. Apoptosis of cancer cell, signal transduction and phosphatase activity were analyzed after treatments. Combination index (CI) was applied to determine the synergistic effects of PA and taxol. Co-immunoprecipitation (co-IP) and proximity ligation assay (PLA) were used to identify in vivo binding between SET and PP2A. In vivo anti-tumor effects of treatment containing PA and taxol were also determined in A549 xenografted mice. Results: After treating the cancer cells with PA and taxol, apoptosis of cancer cells, in concordance with enhancing PP2A-dependent p-Akt downregulation, were observed in a dose-dependent manner in all EGFR wide-type NSCLC cell lines. CI determined by the results of sub-G1 analysis confirmed the synergy between PA and taxol. Overexpression of Akt and inhibition of PP2A diminished the therapeutic effects of this combination. By two different strategies, co-IP and PLA, we found that this combination treatment inhibited the association of SET and PP2A within lung cancer cells. When overexpression SET in treated cancer cells, the therapeutic effects of this combination were abolished. The anti-tumor effects of treatment combining PA and taxol were also validated in A549 xenografted mice. Our data suggested that PP2A inactivation determines the drug sensitivity of taxol in lung cancer cells, and by interfering the binding of SET and PP2A, PA significantly promote PP2A activity and increase the cytotoxic effects of taxol in EGFR wide-type NSCLC. Conclusion: By interfering the binding of SET to PP2A, the novel PP2A enhancer, PA, is shown to reactivate PP2A and work synergistically with taxol for the treatment of EGFR wide-type NSCLC. Citation Format: Man-Hsin Hung, Chung-Wai Shiau, Yung-Jen Hsiao, Hui-Chuan Yu, Wei-Tien Tai, Chun-Yu Liu, Cheng-Yi Wang, Kuen-Feng Chen. Suppressing SET reactivates PP2A function in EGFR wide-type NSCLC and synergizes with taxol to exert anti-cancer effects. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2924. doi:10.1158/1538-7445.AM2015-2924