Jiannong Li1, Jean Viallet, Eric B Haura. 1. Thoracic Oncology and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, MRC3 East, Tampa, FL 33612-9497, USA.
Abstract
PURPOSE: Overexpression of Bcl-2 family members as well as deregulated apoptosis pathways are known hallmarks of lung cancer. Non-small cell lung cancer (NSCLC) cells are typically resistant to cytotoxic chemotherapy and approaches that alter the balance between pro-survival and pro-death Bcl-2 family members have shown promise in preclinical models of NSCLC. METHODS: Here we evaluated the effects of a novel pan-Bcl-2 inhibitor GX15-070 on NSCLC survival and when combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as well as traditional cytotoxic agents. GX15-070 is a small molecule agent that binds anti-apoptotic Bcl-2 proteins and interferes with their ability to interact with pro-apoptotic proteins. We evaluated the effect of GX15-070 and correlated the effect on EGFR status as well as Bcl-2 family protein expression. RESULTS: We show that GX15-070 can disrupt Mcl-1:Bak interactions in lung cancer cells. We identified differential sensitivity of a panel of lung cancer cells to GX15-070 and no clear relationship existed between EGFR status or Bcl-2 family protein expression and sensitivity to GX15-070. GX15-070 could induce apoptosis in a subset of lung cancer cell lines and this correlated with the effects on cell viability. GX15-070 combined with gefitinib was synergistic in a cell line dependent on EGFR for survival but GX15-070 could not reverse resistance to gefitinib in cell lines not dependent on EGFR for survival. Finally, we observed synergy between GX15-070 and cisplatin in NSCLC cells. CONCLUSIONS: Based on these results, GX15-070 can trigger apoptosis in NSCLC cells and can enhance chemotherapy-induced death. These data suggest that clinical trials with GX15-070 in combination with cytotoxic chemotherapy are indicated.
PURPOSE: Overexpression of Bcl-2 family members as well as deregulated apoptosis pathways are known hallmarks of lung cancer. Non-small cell lung cancer (NSCLC) cells are typically resistant to cytotoxic chemotherapy and approaches that alter the balance between pro-survival and pro-deathBcl-2 family members have shown promise in preclinical models of NSCLC. METHODS: Here we evaluated the effects of a novel pan-Bcl-2 inhibitor GX15-070 on NSCLC survival and when combined with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as well as traditional cytotoxic agents. GX15-070 is a small molecule agent that binds anti-apoptotic Bcl-2 proteins and interferes with their ability to interact with pro-apoptotic proteins. We evaluated the effect of GX15-070 and correlated the effect on EGFR status as well as Bcl-2 family protein expression. RESULTS: We show that GX15-070 can disrupt Mcl-1:Bak interactions in lung cancer cells. We identified differential sensitivity of a panel of lung cancer cells to GX15-070 and no clear relationship existed between EGFR status or Bcl-2 family protein expression and sensitivity to GX15-070. GX15-070 could induce apoptosis in a subset of lung cancer cell lines and this correlated with the effects on cell viability. GX15-070 combined with gefitinib was synergistic in a cell line dependent on EGFR for survival but GX15-070 could not reverse resistance to gefitinib in cell lines not dependent on EGFR for survival. Finally, we observed synergy between GX15-070 and cisplatin in NSCLC cells. CONCLUSIONS: Based on these results, GX15-070 can trigger apoptosis in NSCLC cells and can enhance chemotherapy-induced death. These data suggest that clinical trials with GX15-070 in combination with cytotoxic chemotherapy are indicated.
Authors: Jimmy J Hwang; John Kuruvilla; David Mendelson; Michael J Pishvaian; J F Deeken; Lillian L Siu; Mark S Berger; Jean Viallet; John L Marshall Journal: Clin Cancer Res Date: 2010-06-10 Impact factor: 12.531
Authors: Jun Wei; John L Stebbins; Shinichi Kitada; Rupesh Dash; William Placzek; Michele F Rega; Bainan Wu; Jason Cellitti; Dayong Zhai; Li Yang; Russell Dahl; Paul B Fisher; John C Reed; Maurizio Pellecchia Journal: J Med Chem Date: 2010-05-27 Impact factor: 7.446
Authors: Jun Wei; Shinichi Kitada; John L Stebbins; William Placzek; Dayong Zhai; Bainan Wu; Michele F Rega; Ziming Zhang; Jason Cellitti; Li Yang; Russell Dahl; John C Reed; Maurizio Pellecchia Journal: J Med Chem Date: 2010-10-29 Impact factor: 7.446
Authors: Elizabeth A Brem; Karen Thudium; Sapna Khubchandani; Ping-Chiao Tsai; Scott H Olejniczak; Seema Bhat; Wasif Riaz; Jenny Gu; Arshad Iqbal; Ryan Campagna; Joy Knight; Cory Mavis; Paul Hoskin; George Deeb; John F Gibbs; Gerald Fetterly; Myron S Czuczman; Francisco J Hernandez-Ilizaliturri Journal: Br J Haematol Date: 2011-04-15 Impact factor: 6.998