Chordoma Foundation

MAPK

The Mitogen-Activated Protein Kinase pathway includes the genes BRAF, RAS, and ERK1/2.

Location:
BRAF – Chromosome 7q34
KRAS – Chromosome 12p12.1
ERK1 – Chromosome 16p11
ERK2 – Chromosome 22q11

The RAS-RAF-MEK-MAPK pathway is a downstream target of receptor tyrosine kinases like EGFR, c-MET, and PDGFRβ. The MAPK pathway is involved in regulating cell differentiation, proliferation, and antiapoptosis, and abnormal MAPK signaling can therefore play a role in the development and progression of cancer cells.1

MAPK in Chordoma

The MAPK signaling pathway has been shown to be activated in a subset of chordomas. The pathway is a downstream target of a number of receptor tyrosine kinases implicated in chordoma pathogenesis, including EGFR, PDGFRβ, and c-MET. However, few studies have sought to clarify the specific role of the MAPK pathway in chordoma. A chordoma cell line treated with a MAPK inhibitor alongside an mTOR inhibitor did not show increased sensitivity to chemotherapy, and though drugs that inhibit the pathway are being used to treat other cancers, there have been no reports of using them to treat chordoma patients. This page contains a summary of published research exploring the role of MAPK in chordoma.

Molecular Evidence


Copy Number Variation

  • Chromosomal Aberrations: Gains of the region of chromosome 7 region that contains BRAF and of the region of chromosome 12 region that contains KRAS have been observed in the chordoma cell line MUG-Chor1.2
  • Gene Copy Number Variation:Though duplication of the BRAF gene is known to be oncogenic, no tandem duplication has been detected in chordoma (an abnormality known to be oncogenic).3

Somatic Mutation

  • Aside from a single heterozygous mutation detected in the KRAS gene in one chordoma sample, no common or activating mutations have been found within KRAS or BRAF mutational hotspots.4 5 6 7 8

Protein Expression

  • One study showed that MAPK pathway proteins ERK1 and ERK2 were highly expressed phosphorylated in chordoma samples.5 Another study showed expression in 25/42 samples and found expression to be correlated with tumor size.9 MAPK is expressed in chordoma cell lines.10
  • A retrospective study of 35 clival chordoma patients found that progression free survival was significantly longer in patients with low ERK expression compared with high ERK expression and low ERK expression was associated with radiation sensitivity.11

Protein Activation

  • p-ERK1/2 has been detected in the majority of chordoma samples tested.5 12 p-MAPK is differentially expressed in chordoma cell lines and does not correlate to receptor expression.10

Pathway Activation

  • miRNA expression profiling has revealed significant downregulation of miRNAs that target the genes of the MAPK pathway. The subsequent lack of regulation by miRNAs may lead to pathway enrichment through overexpression of its component genes.13 14
  • Phosphorylation of the S6 protein, often activated by mTOR, has been noted even in the absence of mTOR, indicating that its other regulator, the MAPK pathway, is active.5
  • Gene loci that were found to be hypermethylated in cancer samples versus controls fell into a number of cancer-related pathways, including the RAS/MAPK pathway.15

Preclinical Evidence


In-vitro Efficacy

  • U-0126: The MAPK pathway inhibitor U-0216 was unable to suppress S6 phosphorylation in the U-CH1 cell line.16 When cell line U-CH1 was treated with U-0216 alongside mTOR inhibitor rapamycin, it did not increase rapamycin-mediated cytotoxicity.4

References

1.
Dhillon A, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279-3290. [PubMed]
2.
Rinner B, Froehlich E, Buerger K, et al. Establishment and detailed functional and molecular genetic characterisation            of a novel sacral chordoma cell line, MUG-Chor1. Int J Oncol. 2012;40(2):443-451. [PubMed]
3.
Shalaby A, Presneau N, Ye H, et al. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol. 2011;223(3):336-346. [PubMed]
4.
Ricci-Vitiani L, Runci D, D’Alessandris Q, et al. Chemotherapy of skull base chordoma tailored on responsiveness of patient-derived tumor cells to rapamycin. Neoplasia. 2013;15(7):773-782. [PubMed]
5.
Tamborini E, Virdis E, Negri T, et al. Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas. Neuro Oncol. 2010;12(8):776-789. [PubMed]
6.
Shalaby A, Presneau N, Idowu B, et al. Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas. Mod Pathol. 2009;22(8):996-1005. [PubMed]
7.
Le L, Nielsen G, Rosenberg A, et al. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846. [PubMed]
8.
Tauziéde-Espariat A, Bresson D, Polivka M, et al. Prognostic and Therapeutic Markers in Chordomas: A Study  of 287 Tumors. J Neuropathol Exp Neurol. 2016;75(2):111-120. [PubMed]
9.
Zhang K, Chen H, Zhang B, et al. Overexpression of Raf-1 and ERK1/2 in sacral chordoma and association with tumor recurrence. Int J Clin Exp Pathol. 2015;8(1):608-614. [PubMed]
10.
Magnaghi P, Salom B, Cozzi L, et al. Afatinib is a new therapeutic approach in chordoma with a unique ability to target EGFR and Brachyury. Mol Cancer Ther. December 2017. [PubMed]
11.
Zhai Y, Bai J, Wang S, et al. Aberrant expression of ERK and HPGD indicates radiation resistance and poor prognosis for patients with clival chordomas. W. April 2018. doi:10.1016/j.wneu.2018.03.216
12.
Fasig J, Dupont W, LaFleur B, Olson S, Cates J. Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma. Neuropathol Appl Neurobiol. 2008;34(1):95-104. [PubMed]
13.
Long C, Jiang L, Wei F, et al. Integrated miRNA-mRNA analysis revealing the potential roles of miRNAs in chordomas. PLoS One. 2013;8(6):e66676. [PubMed]
14.
Chen K, Chen H, Zhang K, et al. MicroRNA profiling and bioinformatics analyses reveal the potential roles of microRNAs in chordoma. Oncol Lett. 2017;14(5):5533-5539. [PMC]
15.
Alholle A, Brini A, Bauer J, et al. Genome-wide DNA methylation profiling of recurrent and non-recurrent chordomas. Epigenetics. 2015;10(3):213-220. [PubMed]
16.
Han S, Polizzano C, Nielsen G, Hornicek F, Rosenberg A, Ramesh V. Aberrant hyperactivation of akt and Mammalian target of rapamycin complex 1 signaling in sporadic chordomas. Clin Cancer Res. 2009;15(6):1940-1946. [PubMed]