p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs

Abstract

AbstractMalignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity.TP53mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlyingTP53-mediated therapy responses are unclear in the context ofNF1-deficiency. We evaluated the role of two commonly altered genes,METandTP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed thatMETamplification occurs early in human MPNST progression and thatTrp53loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity.Trp53loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes inTrp53-deficient lines suggestingTrp53loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.