MAPK

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
• Preclinical Evidence

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