Therapeutic Targeting of Receptor Tyrosine Kinase Hierarchies in Schwann Cell Neoplasms

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms derived from the Schwann cell
lineage that occur commonly in patients with neurofibromatosis type 1 (NF1) as well as sporadically in the
general population. The prognosis for patients with an MPNST is grim, as current radio- and chemo-
therapeutic regimens are ineffective. Ras hyperactivation, which results from loss of functional NF1, typically in
combination with other tumor suppressor mutations (CDKN2A, TP53, or SUZ12), is characteristic of MPNSTs.
This suggests that inhibiting Ras signaling would be an effective means of treating MPNSTs. However, Ras
has proven to be difficult to directly target therapeutically and drugs targeting Ras effector pathways have not
been effective in patients with MPNSTs. This led us to investigate the effectiveness of therapeutically targeting
key upstream activators of Ras, such as receptor tyrosine kinases (RTKs) in MPNSTs. We examined the role
of all 58 RTKs in sporadic and NF1-associated MPNST cell lines using both pharmacologic and genome-scale
shRNA screens coupled with comprehensive genomic analyses. Our RTK-based pharmacologic screens
established that the broad-spectrum ERBB inhibitor canertinib and the IGF1 receptor (IGF1R) inhibitor
picropodophyllin effectively inhibited MPNST growth and Ras activation. In keeping with these results, our
genome-scale shRNA screens established ERBB3 and IGF1R as essential for the growth of MPNST cells.
Based on these findings, we hypothesize that MPNST growth in vivo is dependent on the action of
ERBB3 and IGF1R and that therapeutic regimens simultaneously targeting these key RTKs will
effectively treat MPNSTs. We will rigorously test this hypothesis in three Specific Aims. In Specific Aim 1, we
will test the hypothesis that combinatorial therapies targeting ERBB receptors and IGF1R will effectively inhibit
MPNST xenograft growth in vivo. We will also determine if other RTKs are reproducibly activated to promote
resistance to ERBB and IGF1R inhibitors and tumor recurrence. In Specific Aim 2, we will test the in vivo role
of ERBB3 in tumor initiation and drug sensitivity using xenografts and a genetically engineered mouse model
(GEMM). In Specific Aim 3, we will test the hypothesis that drug relapse is mediated by “secondary” RTKs that
compensate for ERBB and IGF1R inhibition to drive key cytoplasmic signaling pathways. This experimental
plan will thus allow us to logically develop effective therapies for a currently untreatable type of sarcoma. As
NF1 mutations and Ras hyperactivation are increasingly recognized in other sporadic tumor types, our
approach has broader application to many other types of human cancers.!

Grant Number: 5R01NS109655-05
NIH Institute/Center: NIH
Principal Investigator: STEVEN CARROLL