title: The pan erbB inhibitor PD168393 enhances lysosomal dysfunction-induced apoptotic death in malignant peripheral nerve sheath tumor cells.
abstract: Malignant peripheral nerve sheath tumors (MPNSTs) are rapidly progressive Schwann cell neoplasms. The erbB family of membrane tyrosine kinases has been implicated in MPNST mitogenesis and invasion and, thus, is a potential therapeutic target. However, tyrosine kinase inhibitors (TKIs) used alone have limited tumoricidal activity. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some cases. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival, caspase activation, and autophagy. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells that was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed following the induction of chloroquine (CQ)-induced lysosomal stress. In CQ-treated cells, suppression of autophagy was accompanied by increased caspase activation. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly because of Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.
authors.affiliation: Departments of Pathology, University of Alabama at Birmingham, WP P210, 619 South 19th St, Birmingham, AL 35294-0017, USA.
authors.forename: Latika
authors.initials: L
authors.lastname: Kohli
authors.forename: Niroop
authors.initials: N
authors.lastname: Kaza
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lavalley
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Turner
authors.forename: Stephanie
authors.initials: S
authors.lastname: Byer
authors.forename: Steven L
authors.initials: SL
authors.lastname: Carroll
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D018815:Genes, erbB / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects*; D058990:Molecular Targeted Therapy; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C509204:PD168393; D011799:Quinazolines; D002738:Chloroquine; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020169:Caspases