TY - JOUR T1 - Lapatinib and Obatoclax Kill Breast Cancer Cells through Reactive Oxygen Species-Dependent Endoplasmic Reticulum Stress JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1217 LP - 1229 DO - 10.1124/mol.112.081539 VL - 82 IS - 6 AU - Nichola Cruickshanks AU - Yong Tang AU - Laurence Booth AU - Hossein Hamed AU - Steven Grant AU - Paul Dent Y1 - 2012/12/01 UR - http://molpharm.aspetjournals.org/content/82/6/1217.abstract N2 - Previous studies showed 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 phosphatase and tensin homolog (PTEN) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null breast cancer cells restored drug sensitivity. Coadministration of lapatinib with obatoclax elicited autophagic cell death that was attributable to the actions of mitochondrial reactive oxygen species. Wild-type cells but not mitochondria-deficient rho-zero cells were radiosensitized by lapatinib and obatoclax treatment. Activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase 1/2 (JNK1/2) by the drug combination was enhanced by radiation, and signaling by p38 MAPK and JNK1/2 promoted cell killing. In immunohistochemical analyses, the autophagosome protein p62 was determined to be associated with protein kinase-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1, as well as with binding immunoglobulin protein/78-kDa glucose-regulated protein, in drug combination-treated cells. Knockdown of PERK suppressed drug-induced autophagy and protected tumor cells from the drug combination. Knockdown of PERK suppressed the reduction in Mcl-1 expression after drug combination exposure, and overexpression of Mcl-1 protected cells. Our data indicate that mitochondrial function plays an essential role in cell killing by lapatinib and obatoclax, as well as radiosensitization by this drug combination. ER -