Activation of Receptor Tyrosine Kinases Mediates Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors.

Abstract

Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of malignant peripheral nerve sheath tumors (MPNST). A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an in vitro model of MEKi resistance provided a rationale for combination therapies. HGF/MET signaling was elevated in the MEKi-resistant model. HGF overexpression conferred resistance to MEKi in parental cells. Depletion of HGF or MET restored sensitivity of MEKi-resistant cells to MEKi. Finally, a combination of MEK and MET inhibition demonstrated activity in models of MPNST and may therefore be effective in patients with MPNST harboring genetic alterations in NF1. SIGNIFICANCE: This study demonstrates that MEKi plus MET inhibitor may delay or prevent a novel mechanism of acquired MEKi resistance, with clinical implications for MPNST patients harboring NF1 alterations.

• Authors: Jiawan Wang, Kai Pollard, Ana Calizo, Christine A Pratilas
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 3 Pg. 747-762 (02 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33203698 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• HGF protein, human
• NF1 protein, human
• Neurofibromin 1
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• trametinib
• Hepatocyte Growth Factor
• MTOR protein, human
• MET protein, human
• Proto-Oncogene Proteins c-met
• Receptor Protein-Tyrosine Kinases
• Receptor, Platelet-Derived Growth Factor beta
• Proto-Oncogene Proteins c-raf
• TOR Serine-Threonine Kinases
• PTPN11 protein, human
• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• ras Proteins

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects, genetics)
• Enzyme Activation
• Female
• Hepatocyte Growth Factor (metabolism)
• Humans
• MAP Kinase Signaling System
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Recurrence, Local (drug therapy, enzymology, genetics, mortality)
• Nerve Sheath Neoplasms (drug therapy, enzymology, genetics, mortality)
• Neurofibromatosis 1 (complications, metabolism)
• Neurofibromin 1 (deficiency, genetics)
• Protein Kinase Inhibitors (therapeutic use)
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (antagonists & inhibitors, metabolism)
• Proteomics
• Proto-Oncogene Proteins c-met (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-raf (metabolism)
• Pyridones (pharmacology)
• Pyrimidinones (pharmacology)
• Random Allocation
• Receptor Protein-Tyrosine Kinases (metabolism)
• Receptor, Platelet-Derived Growth Factor beta (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Up-Regulation
• ras Proteins (antagonists & inhibitors, metabolism)