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.