PATH-38. ROSETTE-FORMING GLIONEURONAL TUMOR IS DEFINED BY FGFR1 ACTIVATING ALTERATIONS WITH FREQUENT ACCOMPANYING PI3K AND MAPK PATHWAY MUTATIONS

Abstract BACKGROUND Rosette-forming glioneuronal tumor (RGNT) is an uncommon CNS tumor originally described in the fourth ventricle characterized by a low-grade glial neoplasm admixed with a rosette-forming neurocytic component. METHODS We reviewed clinicopathologic features of 42 patients with RGNT. Targeted next-generation sequencing was performed, and genome-wide methylation profiling is underway. RESULTS The 20 male and 22 female patients had a mean age of 25 years (range 3–47) at time of diagnosis. Tumors were located within or adjacent to the lateral ventricle (n=16), fourth ventricle (15), third ventricle (9), and spinal cord (2). All 31 tumors assessed to date contained FGFR1 activating alterations, either in-frame gene fusion, kinase domain tandem duplication, or hotspot missense mutation in the kinase domain (p.N546 or p.K656). While 7 of these 31 tumors harbored FGFR1 alterations as the solitary pathogenic event, 24 contained additional pathogenic alterations within PI3-kinase or MAP kinase pathway genes: 5 with additional PIK3CA and NF1 mutations, 4 with PIK3CA mutation, 3 with PIK3R1 mutation (one of which also contained focal RAF1 amplification), 5 with PTPN11 mutation (one with additional PIK3R1 mutation), and 2 with NF1 deletion. The other 5 cases demonstrated anaplastic features including hypercellularity and increased mitotic activity. Among these anaplastic cases, 3 harbored inactivating ATRX mutations and two harbored CDKN2A homozygous deletion, in addition to the FGFR1 alterations plus other PI3-kinase and MAP kinase gene mutations seen in those RGNT without anaplasia. CONCLUSION Independent of ventricular location, RGNT is defined by FGFR1 activating mutations or rearrangements, which are frequently accompanied by mutations involving PIK3CA, PIK3R1, PTPN11, NF1, and KRAS. Whereas pilocytic astrocytoma and ganglioglioma are characterized by solitary activating MAP kinase pathway alterations (e.g. BRAF fusion or mutation), RGNT are genetically more complex with dual PI3K-Akt-mTOR and Ras-Raf-MAPK pathway activation. Rare anaplastic examples may show additional ATRX and/or CDKN2A inactivation.

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Functions for Cdc42p BEM adaptors in regulating a differentiation-type MAP kinase pathway

Molecular Biology of the Cell ◽

10.1091/mbc.e19-08-0441 ◽

2020 ◽

Vol 31 (6) ◽

pp. 491-510 ◽

Cited By ~ 3

Author(s):

Sukanya Basu ◽

Beatriz González ◽

Boyang Li ◽

Garrett Kimble ◽

Keith G. Kozminski ◽

...

Keyword(s):

Map Kinase ◽

Rho Gtpases ◽

Rho Gtpase ◽

Mapk Pathway ◽

Map Kinase Pathway ◽

Effector Pathways ◽

Kinase Pathway ◽

Insight Into

How Rho GTPases are directed to effector pathways is an important question. We show here that BEM-type adaptors play unique roles in sequentially directing Cdc42 to an effector MAPK pathway. Our study may provide insight into Rho GTPase specification in other systems.

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Novel Link between PI 3′ Kinase/p38 Map Kinase Pathway in Dasatinib (BMS354825) Mediated Effect in BCR-ABL Expressing Cells.

Blood ◽

10.1182/blood.v110.11.4538.4538 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4538-4538

Author(s):

Crystal Lumby ◽

VeerPal Singh ◽

Shrisha Reddy ◽

Sue Sivess-Franks ◽

Jonathan Dowell ◽

...

Keyword(s):

Map Kinase ◽

Cell Lines ◽

P38 Map Kinase ◽

Pi3 Kinase ◽

Wild Type ◽

Inhibitory Effects ◽

Growth Inhibitory ◽

Map Kinase Pathway ◽

Pi3 Kinase Pathway ◽

Kinase Pathway

Abstract Background: Dasatinib (BMS354825), a dual Src/Abl tyrosine kinase inhibitor, exhibits potent antileukemic effects in vitro and in vivo. Despite the well-established role of BMS354825 in the treatment of imatinib-resistant chronic myelogenous leukemia (CML), the molecular mechanisms that result in generation of antileukemic responses remain unknown. Methods: BCR/ABL (wild type and those carrying mutations: E255K, H396P, Y253F, M351T and T315I) expressing murine BAF3 cell lines were exposed to varying concentrations of BMS354825 for variable times to evaluate for effect on phosphorylation/activation of p38 MAP Kinase and PI3′ Kinase pathway in presence or absence of pharmacologic inhibitors of p38 MAP Kinase and mTOR respectively. Results: In the present study we provide evidence that BMS354825 induces phosphorylation of the p38 MAP Kinase, and activation of its kinase domain, in BCR-ABL expressing cell lines except for those carrying T315I mutation. We also identify the kinases MapKapK-2 which is upregulated in response to BMS354825 as shown by increased phosphorylation of hsp27. Importantly, pharmacological inhibition of p38 MAP Kinase by SB203580 reverses the growth inhibitory effects of BMS354825 on primary leukemic CFU-GM progenitors from patients with CML (see figure). Moreover, SB203580 leads to impairment of the BMS354825 mediated antiproliferative effects in both wild type and mutated CML lines except for those carrying T315I. On the other hand, BMS354825 leads to dephosphorylation of p70S6 Kinase and its downstream effector pathway including down regulation of ribosomal S6. We also report that the pharmacological inhibition of mTOR by Rapamycin augments the growth inhibitory effects of BMS354825 on primary leukemic CFU-GM progenitors from CML patients (see figure). Furthermore, pharmacologic inhibition of p38 MAP Kinase by SB203580 led to reversal of the BMS354825 mediated dephosphorylation of p70 S6 Kinase demonstrating that it maybe downstream of p38 MAP Kinase activation. Altogether, our data establish that activation of the p38 MAP Kinase signaling cascade plays an important role in the generation of the effects of BMS354825 on BCR-ABL expressing cells. Conclusion: We have identified a novel crosstalk mechanism between the p38 MAPK and the PI3′ Kinase pathway which is unique to the effect of BMS354825 in CML. p38 MAP Kinase pathway may play an important role in developing of resistance to BMS354825 in CML. mTOR inhibition may augment effect of BMS354825 in CML and its role in combination with BMS354825 should be explored in resistant disease. Figure Figure

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MEK Inhibition Suppresses Growth of Atypical Teratoid/Rhabdoid Tumors

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlaa042 ◽

2020 ◽

Vol 79 (7) ◽

pp. 746-753

Author(s):

Shubin Shahab ◽

Jeffrey Rubens ◽

Harpreet Kaur ◽

Heather Sweeney ◽

Charles G Eberhart ◽

...

Keyword(s):

Map Kinase ◽

Mitogen Activated Protein Kinase ◽

Low Grade ◽

Mitogen Activated Protein ◽

Atypical Teratoid ◽

Map Kinase Pathway ◽

Rhabdoid Tumors ◽

Pathway Inhibition ◽

Induced Apoptosis ◽

Kinase Pathway

Abstract Atypical teratoid/rhabdoid (AT/RT) tumors are the most common malignant brain tumor of infancy and have a poor prognosis. We have previously identified very high expression of LIN28A and/or LIN28B in AT/RT tumors and showed that AT/RT have corresponding increased expression of the mitogen-activated protein (MAP) kinase pathway. Binimetinib is a novel inhibitor of mitogen-activated protein kinase (MAP2K1 or MEK), and is currently in pediatric phase II clinical trials for low-grade glioma. We hypothesized that binimetinib would inhibit growth of AT/RT cells by suppressing the MAP kinase pathway. Binimetinib inhibited AT/RT growth at nanomolar concentrations. Binimetinib decreased cell proliferation and induced apoptosis in AT/RT cells and significantly reduced AT/RT tumor growth in flank xenografts. Our data suggest that MAP kinase pathway inhibition could offer a potential avenue for treating these highly aggressive tumors.

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The Fission Yeast Mitotic Regulator win1 +Encodes an MAP Kinase Kinase Kinase That Phosphorylates and Activates Wis1 MAP Kinase Kinase in Response to High Osmolarity

Molecular Biology of the Cell ◽

10.1091/mbc.9.8.2325 ◽

1998 ◽

Vol 9 (8) ◽

pp. 2325-2335 ◽

Cited By ~ 52

Author(s):

Itaru Samejima ◽

Shaun Mackie ◽

Emma Warbrick ◽

Ronit Weisman ◽

Peter A. Fantes

Keyword(s):

Cell Cycle ◽

Map Kinase ◽

Cell Cycle Control ◽

Molecular Size ◽

Kinase Domain ◽

Molecular Identity ◽

Map Kinase Pathway ◽

Kinase Pathway ◽

Map Kinase Kinase Kinase ◽

Map Kinase Kinase

The Schizosaccharomyces pombe win1-1 mutant has a defect in the G2-M transition of the cell cycle. Although the defect is suppressed by wis1 + andwis4 +, which are components of a stress-activated MAP kinase pathway that links stress response and cell cycle control, the molecular identity of Win1 has not been known. We show here that win1 + encodes a polypeptide of 1436 residues with an apparent molecular size of 180 kDa and demonstrate that Win1 is a MAP kinase kinase kinase that phosphorylates and activates Wis1. Despite extensive similarities between Win1 and Wis4, the two MAP kinase kinase kinases have distinct functions. Wis4 is able to compensate for loss of Win1 only under unstressed conditions to maintain basal Wis1 activity, but it fails to suppress the osmosignaling defect conferred by win1mutations. The win1-1 mutation is a spontaneous duplication of 16 nucleotides, which leads to a frameshift and production of a truncated protein lacking the kinase domain. We discuss the cell cycle phenotype of the win1-1 cdc25-22 wee1-50mutant and its suppression by wis genes.

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