Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurofibromatosis Type 1 (NF1)-related Malignant Peripheral Nerve Sheath Tumors (MPNST) are highly resistant sarcomas that account for significant mortality. The mechanisms of therapy resistance are not well-understood in MPNSTs, particularly with respect to kinase inhibition strategies. In this study, we aimed to quantify the impact of both the genomic context and targeted therapy on MPNST resistance using reverse phase phosphoproteome array (RPPA) analysis. We treated tumorgrafts from three genetically engineered mouse models using MET (capmatinib) and MEK (trametinib) inhibitors and doxorubicin, and assessed phosphosignaling at 4 h, 2 days, and 21 days. Baseline kinase signaling in our mouse models recapitulated an MET-addicted state (NF1-MET), P53 mutation (NF1-P53), and HGF overexpression (NF1). Following perturbation with the drug, we observed broad and redundant kinome adaptations that extended well beyond canonical RAS/ERK or PI3K/AKT/mTOR signaling. MET and MEK inhibition were both associated with an initial inflammatory response mediated by kinases in the JAK/STAT pathway and NFkB. Growth signaling predominated at the 2-day and 21-day time points as a result of broad RTK and intracellular kinase activation. Interestingly, AXL and NFkB were strongly activated at the 2-day and 21-day time points, and tightly correlated, regardless of the treatment type or genomic context. The degree of kinome adaptation observed in innately resistant tumors was significantly less than the surviving fractions of responsive tumors that exhibited a latency period before reinitiating growth. Lastly, doxorubicin resistance was associated with kinome adaptations that strongly favored growth and survival signaling. These observations confirm that MPNSTs are capable of profound signaling plasticity in the face of kinase inhibition or DNA damaging agent administration. It is possible that by targeting AXL or NFkB, therapy resistance can be mitigated.
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PMID:Kinome Profiling of NF1-Related MPNSTs in Response to Kinase Inhibition and Doxorubicin Reveals Therapeutic Vulnerabilities. 3224 42

Malignant Peripheral Nerve Sheath Tumor (MPNST) is a soft-tissue neurosarcoma. It can occur sporadically, after radiotherapy or in patients with Neurofibromatosis 1 (NF1). The hereditary disorder, NF1, is a common cancer predisposition syndrome. The main genetic feature is the mutation of the NF1 tumor suppressor gene that is inherited in an autosomal dominant, progressive manner. Mutations of the NF1 gene increase the activity of Ras signaling and cause the development of different types of tumors, including subcutaneous and plexiform neurofibromas. These can have further mutations that mediate the transformation into MPNST. Somatic mutations that have been observed are the loss of cell cycle regulators of the CDKN2A gene, and the inactivation of Polycomb Repressive Complex 2 (PRC2), mainly embryonic ectoderm development (EED) or suppressor of zeste 12 homologue (SUZ12). Other molecular pathways that have been targeted for treatment are dual MAPK-mTOR targeting, p53 protein, and MEK-ERK pathway. To advance the therapies focused on delaying or inhibiting malignant tumor formation in NF1, we need to understand the implications of the molecular and genetic pathway that are involved in the transformation into MPNST.
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PMID:Molecular targets for NF1-associated malignant peripheral nerve sheath tumor. 3249 28

Peripheral nerve sheath tumors may occur sporadically or related to neurofibromatosis (NF). Unless the mechanisms of tumorigenesis in NF related malignant peripheral nerve sheath tumors (MPNST) are better understood, it remained unclear in sporadic cases. We aimed to investigate the genetic route for malignancy in both individuals with NF-1 and sporadic ones to open a way for targeted therapies in the future. We investigated the role of HER2 with Dual ISH DNA Probe Cocktail test, BRAF mutation (exon 15) and TERT promoter mutation frequency with Sanger sequencing method in respectively 25 sporadic neurofibromas, 25 NF-1 related neurofibromas and 25 MPNST cases from two institutes. Categorical data were analyzed and summarized as frequency and percentage. Statistical analysis was done with SPSS v.22 statistical package, and the statistical significance level was considered as 0.05. We identified TERT promoter mutation only in one sporadic MPNST (4%) and no BRAF mutation in any case. HER2 amplification is found in 10/25 (40%) MPNST cases. No mutations or gene amplification detected in neurofibromas (p < 0.001). MPNSTs are sarcomas with poor prognosis and limited treatment options. TERT promoter mutations and HER2 amplification may play a putative role in therapeutic purposes.
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PMID:BRAF mutation, TERT promoter mutation, and HER2 amplification in sporadic or neurofibromatosis-related neurofibromas and malignant peripheral nerve sheath tumors: do these molecules have a signature in malignant transformation? 3258 Feb 46

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 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.
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PMID:Activation of receptor tyrosine kinases mediates acquired resistance to MEK inhibition in malignant peripheral nerve sheath tumors. 3320 98

Dysregulation of the receptor tyrosine kinase AXL is known to promote cancer cell growth and survival in many sarcomas, including the rare subtype, malignant peripheral nerve sheath tumors (MPNST). MPNSTs are largely chemoresistant and carry a poor prognosis. AXL is an attractive potential therapeutic target, as it is aberrantly expressed, and its activation may be an early event in MPNST. However, the effect of AXL inhibition on MPNST development and progression is not known. Here, we investigated the role of AXL in MPNST development and the effects of AXL and MEK1/2 co-inhibition on MPNSTs. We used western blotting to examine AXL expression and activation in MPNST cell lines. We analyzed the effects of exogenous growth arrest-specific 6 (GAS6) expression on downstream signaling and the proliferation, migration, and invasion of MPNST cells. The effect of AXL knockdown with or without mitogen-activated protein kinase (MAPK) inhibition on downstream signal transduction and tumorigenesis was also examined in vivo and in vitro. We found that AXL knockdown increased MAPK pathway signaling. This compensation, in turn, abrogated the antitumorigenic effects linked to AXL knockdown in vivo. AXL knockdown, combined with pharmacological MEK inhibition, reduced the proliferation and increased the apoptosis of MPNST cells both in vitro and in vivo. The pharmacological co-inhibition of AXL and MEK1/2 reduced MPNST volumes. Together these findings suggest that AXL inhibition enhances the sensitivity of MPNST to other small molecule inhibitors. We conclude that combination therapy with AXL inhibitor may be a therapeutic option for MPNST.
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PMID:AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors. 3328 92


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