TY - JOUR T1 - Obatoclax and Lapatinib Interact to Induce Toxic Autophagy through NOXA JF - Molecular Pharmacology JO - Mol Pharmacol SP - 527 LP - 540 DO - 10.1124/mol.111.076851 VL - 81 IS - 4 AU - Yong Tang AU - Hossein A. Hamed AU - Nichola Cruickshanks AU - Paul B. Fisher AU - Steven Grant AU - Paul Dent Y1 - 2012/04/01 UR - http://molpharm.aspetjournals.org/content/81/4/527.abstract N2 - Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the B cell CLL/lymphoma-2 (BCL-2) family antagonist obatoclax (GX15-070). Coadministration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial reactive oxygen species generation and increased p62 levels and downstream on activation of p38 mitogen-activated protein kinase and inactivation of mammalian target of rapamycin. By immunohistochemical analysis, in drug combination-treated cells, microtubule-associated protein light chain 3 (LC3) associated with mitochondrial (cytochrome c oxidase), autophagosome (p62), and autolysosome (lysosomal associated membrane protein 2) proteins. Treatment of cells with 3-methyladenine or knockdown of beclin 1 was protective, whereas chloroquine treatment had no protective effect. Expression of myeloid cell leukemia-1 (MCL-1), compared with that of BCL-2 or BCL-2-related gene long isoform, protected against drug combination lethality. Lapatinib and obatoclax-initiated autophagy depended on NOXA-mediated displacement of the prosurvival BCL-2 family member, MCL-1, from beclin 1, which was essential for the initiation of autophagy. Taken together, our data argue that lapatinib and obatoclax-induced toxic autophagy is due to impaired autophagic degradation, and this disturbance of autophagic flux leads to an accumulation of toxic proteins and loss of mitochondrial function. ER -