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Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors.

Publication ,  Journal Article
Peacock, JD; Pridgeon, MG; Tovar, EA; Essenburg, CJ; Bowman, M; Madaj, Z; Koeman, J; Boguslawski, EA; Grit, J; Dodd, RD; Khachaturov, V ...
Published in: Cancer Res
July 1, 2018

Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/ko;lox-stop-loxMETtg/+;Plp-creERTtg/+ ; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1ko/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1ko/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.Significance: Longitudinal genomic analysis reveals a positive selection for MET and HGF copy number gain early in malignant peripheral nerve sheath tumor progression. Cancer Res; 78(13); 3672-87. ©2018 AACR.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2018

Volume

78

Issue

13

Start / End Page

3672 / 3687

Location

United States

Related Subject Headings

  • Triazines
  • Signal Transduction
  • Pyrimidinones
  • Pyridones
  • Proto-Oncogene Proteins c-met
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neurofibromin 1
  • Neurofibromatosis 1
  • Mitogen-Activated Protein Kinase Kinases
 

Citation

APA
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Peacock, J. D., Pridgeon, M. G., Tovar, E. A., Essenburg, C. J., Bowman, M., Madaj, Z., … Steensma, M. R. (2018). Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors. Cancer Res, 78(13), 3672–3687. https://doi.org/10.1158/0008-5472.CAN-17-3167
Peacock, Jacqueline D., Matthew G. Pridgeon, Elizabeth A. Tovar, Curt J. Essenburg, Megan Bowman, Zachary Madaj, Julie Koeman, et al. “Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors.Cancer Res 78, no. 13 (July 1, 2018): 3672–87. https://doi.org/10.1158/0008-5472.CAN-17-3167.
Peacock JD, Pridgeon MG, Tovar EA, Essenburg CJ, Bowman M, Madaj Z, et al. Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors. Cancer Res. 2018 Jul 1;78(13):3672–87.
Peacock, Jacqueline D., et al. “Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors.Cancer Res, vol. 78, no. 13, July 2018, pp. 3672–87. Pubmed, doi:10.1158/0008-5472.CAN-17-3167.
Peacock JD, Pridgeon MG, Tovar EA, Essenburg CJ, Bowman M, Madaj Z, Koeman J, Boguslawski EA, Grit J, Dodd RD, Khachaturov V, Cardona DM, Chen M, Kirsch DG, Maina F, Dono R, Winn ME, Graveel CR, Steensma MR. Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1-Related Malignant Peripheral Nerve Sheath Tumors. Cancer Res. 2018 Jul 1;78(13):3672–3687.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2018

Volume

78

Issue

13

Start / End Page

3672 / 3687

Location

United States

Related Subject Headings

  • Triazines
  • Signal Transduction
  • Pyrimidinones
  • Pyridones
  • Proto-Oncogene Proteins c-met
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neurofibromin 1
  • Neurofibromatosis 1
  • Mitogen-Activated Protein Kinase Kinases