TY - JOUR T1 - Lapatinib and Obatoclax Kill Breast Cancer Cells through ROS-dependent ER Stress JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.081539 SP - mol.112.081539 AU - Nichola Cruickshanks AU - Yong Tang AU - Laurence Booth AU - Hossein Hamed AU - Steven Grant AU - Paul Dent Y1 - 2012/09/18 UR - http://molpharm.aspetjournals.org/content/early/2012/09/18/mol.112.081539.abstract N2 - Prior studies have shown that lapatinib and obatoclax interact in a greater than additive fashion to cause cell death, and do so through a toxic form of autophagy. The present studies sought to extend our analyses. Lapatinib and obatoclax killed multiple tumor cell types, and cells lacking PTEN function were relatively resistant to drug combination lethality: expression of PTEN in PTEN null breast cancer cells restored drug sensitivity. Co-administration of lapatinib with obatoclax elicited autophagic cell death that was due to the actions mitochondrial reactive oxygen species (ROS). Wild type but not mitochondria deficient Rho zero cells were radiosensitized by lapatinib and obatoclax treatment. Activation of p38 MAPK and JNK1/2 by the drug combination was enhanced by radiation and signaling by p38 MAPK and JNK1/2 promoted cell killing. By immunohistochemistry, in drug combination treated cells, the autophagosome protein p62 associated with PERK and IRE1, as well as with GRP78/BiP. Knock down of PERK suppressed drug-induced autophagy and protected tumor cells from the drug combination. Knock down of PERK suppressed the reduction in MCL-1 expression following drug combination exposure; over-expression of MCL-1 protected cells. Collectively, our data argue that mitochondrial function plays an essential role in cell killing by lapatinib and obatoclax treatment was well as radiosensitization by this drug combination. ER -