We previously reported that cooperative RAS-MET signaling drives disease progression in NF1-related MPNSTs, and that MET inhibition results in downstream inhibition of RAS/MAPK in the context of MET amplification. This study revealed that response to MET inhibition appeared to be modulated by P53 gene status. It is currently unclear how P53 function affects kinome signaling and response to kinase inhibition. Here we utilized genetically engineered mouse models with variable levels of Met and Hgf amplification and differential p53 status (NF1fl/KO;lox- stop-loxMETtg/+;Plp-creERTtg/+; NF1+/KO;p53R172H;Plp-creERTtg/+; and NF1+/KO;Plp-creERTtg/+t). These NF1-MPNST models were used to assess a novel MET/MEK (i.e. RAS-MET) inhibition strategy and investigate the adaptive kinome response to MET and MEK inhibition. We demonstrate that combination MET (capmatinib) and MEK (trametinib) inhibition fully suppresses MET, RAS/MAPK, and PI3K/AKT activation in P53 wild type tumors, whereas P53-mutant tumors demonstrated sustained CRAF, BRAF, and AKT activation in the presence of combined MET and MEK inhibition. Interestingly, trametinib therapy alone strongly activates MET signaling in MET and HGF-amplified tumors regardless of P53 status, an effect that was abrogated by the addition of capmatinib. We conclude that P53 alters RAS-MET signaling interactions that drive therapy resistance in NF1-related MPNSTs.

Oncogenic RAS-MET signal interactions are modulated by P53 status in NF1-related MPNSTs