Previous studies in breast cancer cells have shown that Lapatinib (Lap) and Obatoclax (GX) interact in a greater than additive manner to cause cell death. The present studies sought to expand our analyses to CNS (Glioblastoma & Medulloblastoma) tumor cells and to further advance our understanding of the mechanisms of drug action. Combinational treatment with Lap / GX resulted in enhanced tumor cell death in multiple CNS tumor types. Moreover, it was discovered that cells lacking PTEN function were resistant to drug combination lethality and re-expression of PTEN in PTEN null cells restored drug sensitivity. Furthermore, PTEN expressing cancer cells, sensitive to Lap / GX treatment, demonstrated drug resistance upon knockdown of PTEN. Additionally, we established that inhibition of ERBB1 / 3 / 4 receptors was most significant for enhancing GX lethality, and that knockdown of BCL-XL and particularly MCL-1, interacted to facilitate Lap lethality. Pre-treatment of tumor cells in vitro and in vivo with GX enhanced the lethality of Lap to a greater extent than concomitant treatment and suppressed tumor growth. Treatment of animals carrying orthotopic CNS tumor isolates and those implanted with anoikis resistant breast tumors in the brain with Lap / GX prolonged survival. Collectively our data argues that combinational Lap / GX therapy could be of use in the treatment of tumors located in the CNS. Further studies must be carried out in order to elucidate whether autophagy or apoptosis plays the most predominant role in cell death in response to Lap / GX treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2269. doi:1538-7445.AM2012-2269

©2012 American Association for Cancer Research
2012