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Press release
Since the discovery of epidermal growth factor receptor (EGFR) mutations as a key driver mutation in a meaningful subgroup of patients with lung cancer - mainly lung adenocarcinomas, never or former smokers and, more frequently, women - specific treatment with EGFR inhibitors, oral treatments commonly with gefitinib or erlotinib have produced significant improvements in response and duration of response. However, a large proportion of patients develop disease progression after a year or more which can still be partly controlled by continuing treatment with gefitinib or erlotinib and by the addition of chemotherapy to these regimens. In Spain, EGFR mutations occur in nearly 20% of lung adenocarcinoma patients. The drugs currently available are gefitinib and erlotinib and others, representing a second generation of EGFR inhibitors, are in the process of being incorporated into clinical practice.Although mechanisms of resistance to erlotinib or gefitinib have been described, these probably encompass the co-occurrence of pre-existing mutations which are still partly sensitive to the classical EGFR inhibitors.
In this week’s issue of Nature Genetics, the discovery of a new mechanism of resistance to erlotinib or gefitinib in patients with EGFR mutations has been published. This mechanism may explain why responses have only limited durability in many of these patients, generally less than 2 years (though some patients can still be disease free after several years). It must also be recognized that a minority of patients treated with EGFR inhibitors have poor response. Several laboratories in the U.S.A have been working together on identifying the potential mechanism of resistance in these patients with lung cancer driven by EGFR mutations. Along with investigators from South Korea, Pangaea Biotech S.L, Barcelona, joined the research to further characterize the discovery of AXL as a crucial mechanism of acquired resistance.
 
Using microarray technology 21 genes were found to be upregulated in erlotinib resistant transplanted lung tumors in mice. Among the 21 genes which were overexpressed (overactive), AXL was the most. Several experiments in cell lines and in mice demonstrated that AXL and its ligand, GAS6, were significantly overexpressed and treatment with specific AXL inhibitors abrogated tumor growth as well as downstream signaling oncogenic pathways. In the laboratories in Pangaea Biotech S.L, Barcelona and the Catalan Institute of Oncology, Hospital Germans Trias i Pujol quantification of AXL and GAS6 mRNA was performed. AXL and GAS6 mRNA was found to be elevated in 20% and 60% of cases. Also in Seoul, South Korea they verified the acquisition of resistance by overexpression of GAS6 and AXL using immunostaining in rebiopsies of 35 patients who were resistant to gefitinib or erlotinib.
The next actions leading from this work are to validate the findings by whole genome sequencing analysis of tumor tissue, acquired via second biopsy at the time of progression of the disease, for further characterization of this mechanism of resistance. Samples from patients from Badalona, Barcelona, Pamplona, Zurich Switzerland, Limoges France, Bogota Colombia and Atlanta in the U.S have been identified for inclusion in the large scale endeavor. The implications of this work are large-scale endevors which are being made to identify AXL inhibitors in order to open a clinical trial combining erlotinib or gefitinib with an AXL inhibitor. The discovery of AXL predicts the lack of curability of the disease when treated with single type therapy, such as an EGFR inhibitor. In order to extend responses to treatment, the combination of therapies targeting at least two different pathways, for example, inhibition of both EGFR and AXL, is required.
Since the discovery of EGFR mutations, the need for genetic testing in a majority of patients with lung cancer has been identified. To this end a program was created, the Spanish Lung Adenocarcinoma Database (SLADB) under the umbrella organization of the Spanish Lung Cancer Group (SLCG) offering screening of EGFR mutations. The SLADB was the first such program in the world to be implemented. Screening was performed in the Catalan Institute of Oncology laboratory in Badalona. In addition, Dr Rafael Rosell headed the group performing the first trial in non-Asian patients, the EURTAC trial, which has been used for the approval of erlotinib in first line treatment by the European Medical Agency (EMA).
 
Dr Rafael Rosell is Head of Medical Oncology at the Oncology Institute Dr Rosell, USP Dexeus University Institute; Head of Medical Oncology at the Catalan Institute of Oncology, Hospital Germans Trias i Pujol; Chairman and Founder of Pangaea Biotech S.L; President and Founder of the Spanish Lung Cancer Group.