Combinatorial treatment of malignant peripheral nerve sheath tumors with tyrosine kinase inhibitors hinders proliferation and survival
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are the most common cause of death in patients with neurofibromatosis type 1 (NF1). At present, surgery is the only effective means of treating these highly aggressive sarcomas. We have shown that erbB membrane tyrosine kinases promote MPNST proliferation and invasion and that pan‐erbB inhibitors (e.g., canertinib) have potent cytostatic effects on MPNST cells. However, in other tumor types, multiple receptor tyrosine kinases are often coactivated, and combinatorial therapy is required to overcome resistance. To identify additional therapeutic targets, we treated four human MPNST cell lines with tyrosine kinase inhibitors acting on growth factor receptors (PDGF, VEGF, c‐Met, Kit) implicated in MPNST pathogenesis and examined the effects of these agents on proliferation and survival. Both canertinib and sorafenib potently inhibited proliferation and survival, while sunitinib, crizotinib and sorafenib were ineffective. Simultaneous treatment with canertinib and sorafenib additively inhibited survival, suggesting that combinatorial therapy with these agents may be effective against MPNSTs in vivo, a possibility that we are currently testing in orthotopically xenografted mice. We are also using kinomics to identify kinases impacted by canertinib and sorafenib that may represent additional therapeutic targets in MPNSTs. Funded by NIH and DOD.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 01, 2013
- Source ID
- 10.1096/fasebj.27.1_supplement.1088.4
Entities
People
- Kevin Aaron Roth
- Stephanie Nicole Brosius
- Steven Lewis Carroll
Organizations
- National Institutes of Health
- United States Department of Defense
- University of Alabama at Birmingham