Chordoma Foundation


Epidermal Growth Factor Receptor (EGFR) is a receptor tyrosine kinase (RTK). RTKs code for proteins on the surface of the cell that become activated when their ligands bind and dimerize.

Ligands: EGF, TGFα, and others
Location: Chromosome 7p12

Activation of EGFR
leads to the phosphorylation of signaling proteins involved in downstream pathways, including PI3k-Akt-mTOR and RAS-RAF-MEK-MAPK. Both pathways are critical in regulating cellular apoptosis, proliferation, migration, and survival. Over-expression of EGFR, by disrupting the function of these pathways, can increase cellular proliferation and contribute to aggressive tumor behavior.

EGFR in Chordoma

Aberrant activation of receptor tyrosine kinases is implicated in a wide variety of human cancers. Of the RTKs activated in chordoma, EGFR is most commonly and strongly activated, with the majority of samples found to have high levels of the activated EGFR protein. A number of drugs have been designed to prevent the activation of EGFR. Treating chordoma cell lines with these EGFR inhibitors has decreased the size and density of chordoma cells and led to reduced cell line growth. EGFR inhibitors are being tested in clinical trials that include chordoma patients. This page contains a summary of published research evaluating EGFR inhibition as a potential treatment for chordoma.

Molecular Evidence

Copy Number Variation

Chromosomal Aberrations: Chromosome 7 gains and partial polysomies are among the most common chromosomal aberrations observed in chordomas.1 2 3 4 5 6 7 8 9 10

EGFR Gene Copy Number Variation: EGFR gene polysomies have been detected in a number of chordomas tested, and focal amplification has been reported in a small fraction; however, the EGFR gene has not been found to be amplified consistently.9 11 12 13

Germline Genetic Variant

44/62 chordoma samples demonstrated a SNP (ID: rs1050171) in exon 20 of the tyrosine kinase domain of EGFR that involved a silent mutation of G to A in glutamine (number 787, cDNA position 2607).6

Somatic Mutation

No activating mutations have been found within the sequence of the EGFR gene.3 6 11 13 14

Gene Expression

EGFR and EGFR ligands are highly expressed at the gene level in chordoma samples11 and expression is upregulated in chordoma samples versus controls.15 16

Increased expression of the EGFR activator TNF-α was associated with shorter progression-free survival (PFS) in a cohort of 46 chordoma patients.17

YBX1 binds to the EGFR promoter to increase EGFR expression. YBX1 expression is higher in chordoma tumors compared to distant normal tissues.18

Protein Expression

EGFR is detected in the majority of chordoma samples tested (including primary and advanced cases as well as pediatric and adult) and in the chordoma cell lines UCH-1, UCH-2, MUG-Chor1, UM-Chor1, Chor-IN-1, and JHC7.3 5 6 9 11 12 13 14 19 20 21 22 23 24 25 26 27 28 29 30 31

EGFR protein levels are inversely correlated with miRNA-608 expression and miRNA-608 is downregulated in chordoma cell lines. EGFR is predicted to be a target of miRNA-608 in chordoma.32

Protein Activation

p-EGFR, the phosphorylated/active form of the EGFR protein, is detected in UCH-1 and in virtually all chordomas studied by immunohistochemistry and RTK antibody arrays.3 6 11 13 19

Preclinical Evidence

In-vitro Efficacy

  • Tyrphostin: Treatment of the chordoma cell line UCH-1 with the EGFR tyrosine kinase inhibitor tyrphostin (AG1478) led to cell spindling, reduced cell size, and decreased cell density. Tyrphostin inhibited growth in a reversible, dose-dependent manner and progressively reduced cell number over the course of 7 days, leading to reduced phosphorylation of EGFR.13
  • Gefitinib: Treatment of U-CH1 inhibited cellular proliferation in a dose-dependent fashion.33 A subsequent study confirmed U-CH1’s response to gefetinib, and found that U-CH7, UM-Chor1, and MUG-Chor1 also responded; apoptosis was induced in a dose-dependent manner.34
  • Erlotinib: Treatment of U-CH1 inhibited cellular proliferation in a dose-dependent fashion.33 As they did for gefitinib, Scheipl et al. confirmed U-CH1’s response to erlotinib, and found that U-CH7, UM-Chor1, and MUG-Chor1 also responded. Again, apoptosis was induced in a dose-dependent manner.34
  • Sapatinib: Four cell lines (U-CH1, U-CH7, UM-Chor1, and MUG-Chor1) of seven tested responded to treatment with sapatinib. Inhibition of p-EGFR and downstream
    targets occurred at lower doses with sapitinib than with other EGFR inhibitors tested.34
  • Sapatinib + Crizotinib: c-MET signaling was activated in the most resistant cell line (U-CH2) of the seven tested, and a combination of the c-MET inhibitor crizotinib and the EGFR-inhibitor sapitinib exhibited a synergistic effect on cell kill.34
  • Afatinib (BIBW292): When tested on seven cell lines, afatanib achieved a significant kill effect on UM-Chor1 cells and inhibited growth of U-CH1 and MUG-Chor1.34
  • Poziotinib (NOV120101; HM781-36B): When tested on seven cell lines, poziotinib inhibited growth of U-CH1, MUG-Chor1, and UM-Chor1.34
  • Lapatinib: When tested on seven cell lines, lapatinib was potent on UM-Chor1 and showed moderate activity on MUG-Chor1.34
  • Cetuximab + natural killer (NK) cells: Treatment of the chordoma cell lines JHC7, UM-CHor1, U-CH2 and MUG-Chor1 with cetuximab and NK cells from healthy donors caused lysis of chordoma cells via antibody-dependent cell-mediated cytotoxicity (ADCC). NK cells that expressed FcgRIIIa-158 VV induced higher cetuximab-mediated ADCC of chordoma cells, suggesting that cetuximab therapy could lead to a better clinical outcome for chordoma patients who have NK cells expressing the CD16 V158 FcgRIIIa receptor allele.27
  • Erlotinib and miRNA-608: Transfection of chordoma cell lines with pre-miRNA-608 inhibited cell proliferation, survival and invasion similar to treatment with Erlotinib.32
  • Erlotinib, gefitinib, lapatinib, neratinib, dacomitinib: Treatment of six chordoma cell lines with each of these EGFR/HER2 family inhibitors found that these drugs were effective in two cell lines, U-CH1 and UM-Chor1, but were not active in the remaining four cells lines.29
  • Osimertinib and rociletinib: These T790M EGFR mutant-selective inhibitors were inactive or poorly active in six chordoma cell lines, as expected due to the absence of EGFR mutations in those cell lines.29
  • Afatinib: The EGFR inhibitor afatinib had anti-proliferative activity in 5 of 6 chordoma cell lines tested, with IC50s ranging from 0.01 to 0.7μM. Afatinib was found to promote degradation of EGFR and brachyury, both of which are crucial to chordoma cell growth, and the sensitivity of chordoma cell lines to afatinib was found to correlate with EGFR phosphorylation and expression of AXL and STK33. 29
  • A panel of 16 molecules designed to target EGFR and GAK were screen for efficacy in five chordoma cell lines and showed varying degrees of efficacy.35
  • A panel of molecules targeting the EGFR active site water network identified a compound that is the most potent inhibitor to date of the chordoma cell line U-CH2.36

In-vivo Efficacy

  • Erlotinib: Treatment of a patient-derived xenograft with erlotinib resulted in a significantly lower tumor volume than was observed in controls (411.3 mm3 versus 1433 mm3), and molecular analyses revealed reduced phosphorylation of the Tyr845 residue of EGFR.33
  • Lapatinib: Treatment of an EGFR-expressing xenograft induced low-level, heterogeneous switching-off of EGFR and its downstream signaling effectors.37
  • Afatinib: Treatment of three patient-derived xenograft mouse models and one cell-line xenograft mouse model with 20mg/kg afatinib resulted in potent tumor growth inhibition in all models with no signs of toxicity.29
  • Overexpression of EGFR and VEGFR2 (KDR) potently induced a chordoma phenotype in zebrafish, yet overexpression of Brachyury did not.38

Clinical Evidence

Case Reports and Case Series

There have been a number of case reports and case series detailing the results of treating chordoma patients with therapeutic agents that target EGFR.

  • Cetuximab/Gefitinib: One case reported that treatment with these EGFR inhibitors had invoked a partial response of lung metastases in a patient with sacral chordoma.39 Another reported that it had reduced spinal compression and led to tumor shrinkage in a patient with cervical chordoma.40
  • Cetuximab/Gefitinib or Erlotinib: In eight patients with neurological symptoms caused by chordoma, four of the six evaluable experienced some level of neurological improvement. Three also experienced improvements in mobility.41
  • Erlotinib: In one report, a patient with advanced, EGFR-expressing chordoma who had advanced on Imatinib (a PDGFR inhibitor) responded to Erlotinib during 12 months of treatment.42 In another report, a patient with sacral chordoma experienced a reduction in tumor bulk over 3 months of treatment.43
  • Erlotinib: A patient’s clival tumor progressed after 5 months treatment with Imatinib (a PDGFR inhibitor). Subsequent treatment with Erlotinib led to partial response of the tumor, which had been sustained for 28+ months as of July 2014.44
  • Erlotinib: A patient with sacral chordoma was treated with the PDGFR inhibitor imatinib for 4 months until slight progression occurred and then the mTOR inhibitor everolimus was added and stable disease was achieved for 16 months. After disease progression, the patient was treated with erlotinib which led to a brief clinical benefit.45
  • Erlotinib + Cetuximab, followed by Erlotinib + Bevacizumab: A patient was treated with an unresected skull-based tumor was treated with Erlotinib and Cetuximab. When PET scan indicated no reduction in tumor methionine uptake, Cetuximab was replaced with Bevacizumab (a VEGF inhibitor). Methionine uptake decreased and MRI revealed a clear reduction in contrast enhancement and a slight decrease in tumor size.46 Patient remains stable 4.5 years after Erlotinib/Bevacizumab treatment began. Another patient was treated with erlotinib and briefly with cetuximab. Her clival tumor was stable for 2 years stable on erlotinib alone. After the patient progressed, bevacizumab was added to her treatment regimen for 2 months and brought instant relief of neurological pain. Erlotinib treatment continued, and the disease has remained stable disease for 2 years.47
  • Erlotinib + Bevacizumab: A patient whose sacral tumor was proliferative was treated for 5 months until she developed a therapy-related infection. Tests revealed that tumor proliferation had stopped. The disease remains stable 2.5 years after treatment.47

Retrospective Studies

  • Erlotinib: A retrospective series of 80 patients found the median PFS was 7.2 months among 62 patients treated with imatinib, 19.2 months among a group of 13 patients treated sorafenib (n=11), sunitinib (n=1), and temsirolimus (n=1), and 14.7 months among 5 patients treated with erlotinib. There were no statistically significant differences between imatinib versus the group (sorafenib, sunitinib, and temsirolimus), erlotinib versus this group, or erlotinib versus imatinib.48

Phase I Trials

  • Erlotinib + Linsitinib: A spinal chordoma patient was among the 5 (of 75) evaluable patients with advanced solid tumors who experienced partial response to treatment with EGFR inhibitor erlotinib and IGF1R inhibitor Linsitinib (OSI-906). Partial response was sustained 268+ weeks after treatment initiation.49 50

Phase II Trials

  • Lapatinib: A phase II study in 18 patients with advanced, EGFR-expressing chordoma assessed the efficacy of Lapatinib, an EGFR and HER2/neu inhibitor, in treating chordoma. Six patients showed partial response to treatment, seven maintained stable disease, and five progressed. Overall Response Rate (ORR), the primary endpoint, was 33.3% (6 of 18 patients).51

Open Clinical Trials

The following clinical trials have been launched to explore whether targeting EGFR is effective in treating chordoma patients. Visit our Clinical Trials page to view a list of other clinical trials available to chordoma patients and to find out who to contact if you wish to participate.

Trial Identifier



NCT03083678 Afatinib in Locally Advanced and Metastatic Chordoma Leiden University Medical Center (Netherlands)

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