TY - JOUR
T1 - p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs
AU - Grit, Jamie L.
AU - McGee, Lauren E.
AU - Tovar, Elizabeth A.
AU - Essenburg, Curt J.
AU - Wolfrum, Emily
AU - Beddows, Ian
AU - Williams, Kaitlin
AU - Sheridan, Rachael T.C.
AU - Schipper, Joshua L.
AU - Adams, Marie
AU - Arumugam, Menusha
AU - Vander Woude, Thomas
AU - Gurunathan, Sharavana
AU - Field, Jeffrey M.
AU - Wulfkuhle, Julia
AU - Petricoin, Emanuel F.
AU - Graveel, Carrie R.
AU - Steensma, Matthew R.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/5/3
Y1 - 2024/5/3
N2 - Malignant 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. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss 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. Trp53 loss 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 in Trp53-deficient lines suggesting Trp53 loss 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.
AB - Malignant 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. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss 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. Trp53 loss 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 in Trp53-deficient lines suggesting Trp53 loss 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.
UR - http://www.scopus.com/inward/record.url?scp=85187641412&partnerID=8YFLogxK
U2 - 10.1038/s41388-024-03000-9
DO - 10.1038/s41388-024-03000-9
M3 - Article
C2 - 38480916
AN - SCOPUS:85187641412
SN - 0950-9232
VL - 43
SP - 1411
EP - 1430
JO - Oncogene
JF - Oncogene
IS - 19
ER -