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. 2015 Oct 13;6(31):30929-38.
doi: 10.18632/oncotarget.5131.

Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer

Silvia Park  1 , Emma Langley  2 , Jong-Mu Sun  1 , Steve Lockton  2 , Jin Seok Ahn  1 , Anjali Jain  2 , Keunchil Park  1 , Sharat Singh  2 , Phillip Kim  2 , Myung-Ju Ahn  1
Affiliations

Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer

Silvia Park et al. Oncotarget. .

Abstract

Purpose: Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30-40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response.

Methods: We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment.

Results: As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild-type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 (p = 0.0001), 0.5 vs. 9.3 (p = 0.0006) and 1.0 vs. 11.2 months (p = 0.0008), respectively.

Conclusion: The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors.

Keywords: EGFR TKI; EGFR/MET ratio; HER3; NSCLC; PFS.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors disclose no potential conflicts of interest.

Figures

Figure 1
Figure 1. Expression and Phosphorylation of RTKs and downstream signaling molecules in NSCLC
Immunoarray technology, Collaborative Enzyme Enhanced Reactive-immunoassay (CEER™), was utilized to determine the level of expression and degree of phosphorylation in tumor cells isolated from specimens collected from NSCLC patients. Schematic assay principle and assay format is shown on the left. Each array contains designated standards and controls; multiple photomultiplier (PMT) settings are utilized to have expanded dynamic range of signal quantitation and signals for clinical samples are reported after normalizing against standards on each slide. Capture antibodies printed on microarray surface in triplicate with two dilutions are indicated (right).
Figure 2
Figure 2. Kaplan-Meier analysis of PFS according to baseline EGFR/MET Index in NSCLC patients (N = 27, all genotypes included) treated with EGFR TKIs
A striking separation of PFS was observed between NSCLC patients with high EGFR/MET relative ratio vs. low EGFR/MET relative ratio at multiple cut-offs.
Figure 3
Figure 3. Kaplan-Meier analysis of PFS according to baseline EGFR/MET Index in NSCLC patients with EGFR-activating mutations (N = 15) treated with EGFR TKIs
A striking separation of PFS was observed between NSCLC patients with high EGFR/MET relative ratio vs. low EGFR/MET relative ratio even among patients with EGFR-activating mutations.
See this image and copyright information in PMC

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