Abstract LB-225: EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity

Abstract

Abstract Glioblastoma is the most common and most intractable brain malignancy in adults. Patients with glioblastoma have dismal prognosis with a median survival of 12-14 months. This unfortunate poor prognosis is, in part, due to the aggressive nature of these tumors and the lack of effective therapy. EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report here that in glioblastoma cell lines, xenografts and primary specimens, EGFR and EGFRvIII paradoxically co-express with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. Both EGFR and EGFRvIII bind to PUMA constitutively and under apoptotic stress, and subsequently sequester PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR- and EGFRvIII-expressing glioblastoma cells to EGFR kinase inhibitor, Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR and EGFRvIII that leads to drug resistance of glioblastoma and potentially other tumor types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-225.