title: Lapatinib and obatoclax kill tumor cells through blockade of ERBB1/3/4 and through inhibition of BCL-XL and MCL-1.
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 the central nervous system (CNS) tumor cells and to further define mechanisms of drug action. Lapatinib and obatoclax killed multiple CNS tumor isolates. Cells lacking PTEN (phosphatase and tensin homolog on chromosome 10) function were relatively resistant to drug combination lethality; expression of PTEN in PTEN-null cells restored drug sensitivity, and knockdown of PTEN promoted drug resistance. On the basis of knockdown of ERBB1-4 (erythroblastic leukemia viral oncogene homolog 1-4), 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 knockdown of BCL-xL (B-cell lymphoma-extra large)and MCL-1 (myeloid cell leukemia-1) interacted in an additive fashion to facilitate lapatinib lethality. Pretreatment 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. Altogether, our data show that lapatinib and obatoclax therapy could be of use in the treatment of tumors located in the CNS.
authors.affiliation: Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298-0035, USA.
authors.forename: Nichola
authors.initials: N
authors.lastname: Cruickshanks
authors.forename: Hossein A
authors.initials: HA
authors.lastname: Hamed
authors.forename: M Danielle
authors.initials: MD
authors.lastname: Bareford
authors.forename: Andrew
authors.initials: A
authors.lastname: Poklepovic
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles; D000077341:Lapatinib; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors*; D066247:Receptor, ErbB-4; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D011799:Quinazolines; D051020:bcl-X Protein; D000077341:Lapatinib; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D051059:PTEN Phosphohydrolase; C520962:obatoclax