The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cell

Cancer Cell. 2005 8(4):287-297.

Speaker: 曾昱豪                           Date:14:00~15:00, Feb15, 2006

Commentator: 劉校生老師                   Place: Room 601

Abstract:

    EGFR (HER1) is a member of the HER kinase family. It is activated by ligand-dependent homo and heterodimerization, which stimulates diverse pathways including Ras/Raf/MEK/MAPK, phospholipase C, STAT and PI3K/Akt signaling. EGFR-activated signaling regulates cell cycle progression, proliferation and even inhibits apoptosis. Mutation of EGFR leads to malignant transformation in a variety of tumor. There are more and more inhibitors of HER family tyrosine kinase have been developed, but the clinical effect has been restricted to a small number of patients. Previous studies reveal that proliferation of tumor cells with PTEN mutation is EGFR-independent, but re-expression PTEN sensitizes them to EGFR inhibition². Here the authors uncovered that induction of PTEN expression inhibits Akt activity in PTEN mutation cells, slows their growth, and markedly sensitizes them to induce apoptosis by EGFR inhibitor gefitinib. Inhibition of two parallel pathways EGFR/MAPK and PI3K/Akt synergistically regulate the pro-apoptosis protein BAD no longer phosphorylated on serine 112 and 136, which cause it release from its sequester 14-3-3 protein and induced apoptosis¹. The data reveal that BAD protein acts as a switch that integrates the anti-apoptosis effects in these two pathways, and also brightened a potential clinical role that EGFR inhibitor may be useful in combination with inhibitors of PI3k/Akt kinase signaling for the treatment of tumors in which EGFR activation and PTEN mutation coexist. 

References:

1.She, Q.B. The BAD protein integrates survival signaling by EGFR/MAPK and   PI3K/Akt kinase pathways in PTEN-deficient tumor cell. Cancer Cell. 8,287-97.2005

2.She, Q.B. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3’-kinase/Akt pathway signaling. Clin. Cancer Res. 9, 4340–4346. 2003.