Abstract

Prior studies in breast cancer cells 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 to CNS tumor cells, and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN function were relatively resistant to drug combination lethality: expression of PTEN in PTEN null cells restored drug sensitivity and knock down of PTEN promoted drug resistance. Based on knock down of ERBB1-4, we discovered that the inhibition of ERBB1 / 3 / 4 receptors were most important for enhancing obatoclax lethality, rather than ERBB2. In parallel we noted in CNS tumor cells that knock down of BCL-XL and MCL-1 interacted in an additive fashion to facilitate lapatinib lethality. Pre-treatment of tumor cells with obatoclax enhanced the lethality of lapatinib to a greater extent than concomitant treatment. Treatment of animals carrying orthotopic CNS tumor isolates with lapatinib and obatoclax prolonged survival. Collectively our data argues that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS