%0 Journal Article %A Yong Tang %A Hossein Hamed %A Nichola Cruichshanks %A Paul B Fisher %A Steven Grant %A Paul Dent %T Obatoclax and Lapatinib Interact to Induce Toxic Autophagy Through NOXA %D 2012 %R 10.1124/mol.111.076851 %J Molecular Pharmacology %P mol.111.076851 %X Prior studies demonstrated that resistance to the ERBB1/2 inhibitor lapatinib could be overcome by the BCL-2 family antagonist obatoclax. Co-administration of lapatinib with obatoclax caused synergistic cell killing by eliciting autophagic cell death that was dependent upstream on mitochondrial ROS generation, increased p62 levels, and downstream upon activation of p38 MAPK and inactivation of mTOR. By immunohistochemistry, in drug combination treated cells, LC3 associated with mitochondrial (COX IV); autophagosome (p62) and autolysosome (LAMP2) proteins. Treatment of cells with 3-methyl adenine or knock down of Beclin1 was protective whereas chloroquine treatment had no protective effect. Expression of MCL-1, compared to BCL-2 or BCL-XL, protected against drug combination lethality. Lapatinib and obatoclax initiated autophagy depended on NOXA mediated displacement of pro-survival BCL-2 family member, MCL-1 from Beclin-1, which was essential for the initiation of autophagy. Collectively, our data argue that lapatinib and obatoclax –induced toxic autophagy is due to an impaired autophagic degradation and this disturbance of autophagic flux that leads to an accumulation of toxic proteins and loss of mitochondrial function. %U https://molpharm.aspetjournals.org/content/molpharm/early/2012/01/04/mol.111.076851.full.pdf