Abstract.According to previous reports in the literature, the
T790M mutation indicates an acquired resistance to tyrosine kina inhibitors. The initial positive effect of combination chemotherapy with erlotinib as the first line of treatment correlates with veral positive predictors including the type of carcinoma, non-smoking status, occurrence of rash and the prence of exon 19 EGFR gene mutation. The ca of a 32-year-old, non-smoker with non-contributory history patient,who was diagnod with adenocarcinoma in the left lung T4N0M0 stage IIIB is reported. The patient underwent 6 cycles of chemotherapy with erlotinib, gemcitabine and cisplatin,followed by complete remission. Fifteen months after commencing therapy, dia recurred over subquent therapy with erlotinib and then gefitinib. During that time,bone and cerebral metastas with pericardial effusion were detected. The patient died 7 months later. Genetic examination of tumour tissue collected at the beginning of therapy revealed activating exon 19 mutation in the EGFR gene. Later, during the relap,the same mutation was still prent and, in addition, a T790M mutation in exon 20 of EGFR was found. The subquently acquired resistance against both erlotinib,as well as gefitinib was most likely a result of tumor cells acquiring the T790M mutations and escaping the drug effect. The authors recommend testing for T790M mutation prence in lected patients prior to targeted therapy with tyrosine kina inhibitors.Non-small cell lung cancer (NSCLC) reprents more than 85% of all lung ca
ncer cas. The cytostatic therapy of locally advanced NSCLC followed by pleural effusion is rarely successful. Better prognosis, especially for non-smokers,aris from targeted therapy by suppression of growth factor
signals through the inhibition of the epidermal growth factor receptor (EGFR) (1, 2). The EGFR gene product, a tyrosine kina, has an important function in the transduction of growth signals by phosphorylation of other cascade proteins.The enzymatic reaction takes place at a specific EGFR site,the ATP-binding pocket, which is coded within the range of exons 18 through 21. Blocking of the ATP pocket by low molecular agents deactivates the EGFR function and stops transduction of the growth signal. This principle is utilized by two clinically approved low-molecular tyrosine kina inhibitors: gefitinib (IRESSA ®) and erlotinib (TARCEVA ®).Tyrosine kina activity is tightly regulated in normal cells,but dysregulated due to mutation in some types of cancer,including lung cancer. Malignant cells become dependent on growth signals from the mutant tyrosine kinas (3,4). In mid 2004, two groups independently reported incread clinical respon to gefitinib therapy in patients carrying specific gene mutations within the tyrosine kina ATP box domain (5).The so-called "activating EGFR mutations" mostly included deletions of veral bas in exon 19, followed by less frequent substitutions in exons 18, 20 and 21. A majority of the mutations were detected in
women, non-smokers and in patients with pulmonary adenocarcinomas. A higher frequency was also found in an Asian population compared to Caucasians (5). Since the first reports were published,screening for EGFR mutations has become a major theme in the targeted therapy of NSCLC,with experiments conducted on various populations. Conquently another interesting effect of EGFR mutation was discovered. It was reported that a specific mutation at exon 20 (assigned as T790M substitution) bears a negative prognostic value for targeted gefitinib therapy (6). Unlike in the ca of the infamous exon 18 EGFR activating mutation, patients with the T790M substitution exhibited resistance to the tyrosine kina agent.In this report,we demonstrate an interesting ca of an erlotinib responder bearing an activating EGFR exon 19mutation who subquently developed resistance due to a later appearance of the T790M mutation in the lung adenocarcinoma tissue.
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Correspondence to: Marek Minarik, Ph.D., Laboratory for Molecular Genetics and Oncology, Genomac International, Bavorska 856, CZ-15541, Prague, Czech Republic. Tel: +420 224458048, Fax: +420224458021, e-mail:
储存条件Key Words: NSCLC, EGFR mutation, T790M, erlotinib, gefitinib.
A NTICANCER R ESEARCH 27: 1879-1882(2007)
Acquired Resistance of Pulmonary Adenocarcinoma to Initially Successful Targeted Therapy due to EGFR Mutation T790M
D. JANCARIKOVA 1, M. PESEK 1, L.BENESOVA 3, O. TOPOLCAN 2, L. HOLUBEC Jr.2and M. MINARIK 3关于竹子的古诗
1Department of Tuberculosis and Respiratory Dias, 2Second Department of Internal Medicine, Charles University, Medical School and Teaching Hospital Plzen;
3Laboratory for Molecular Genetics and Oncology, Genomac International,
Prague, Czech Republic
周记初二0250-7005/2007 $2.00+.40
A NTICANCER R ESEARCH 27: 1879-1882(2007)手工小鱼
Figure1.Chest X-ray after the admission to the Pulmonary Department.
Ca Report
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the patient was still being treated with erlotinib. Subquent application of an alternative tyrosine kina inhibitor (gefitinib) and another oncology therapy did not influence further progression.
后背麻The initial reports on the importance of certain EGFR mutations for a positive respon to targeted biological therapy were published after the patient’s death; therefore,all genetic testing was performed post-mortem on archived tissue material. The EGFR testing was directed at mutations in exons 18-21 covering the complete tyrosine-kina domain (Figure 4). A single EGFR mutation, a deletion of veral bas in exon 19,was detected in a sample taken from the tumor prior to erlotinib therapy. This type of mutation is generally assumed to be a predictor for positive respon to tyrosine kina inhibitory agents. In addition, the retrospective analysis performed on the TALENT study data confirmed synergy between chemotherapy and targeted therapy in patients with activating EGFR mutations or non-smoking status (6). Our patient exhibited both of the predictors, hence, the remission was achieved in full
Jancarikova et al : Resistance of Pulmonary Adenocarcinoma due to EGFR Mutation T790M
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Figure
4.The position of T790M mutation in exon 20 of EGFR gene.
Figure 2.CT examination 15 months from the beginning of the therapy.Figure 3.Chest X-ray 21 months from the beginning of the therapy.
agreement with the general expectations. The appearance of a rash further indicated positive respon to erlotinib during the combination treatment (7).薛渊
Tests performed on a sample obtained at the time of dia progression confirmed the exon 19 deletion. In addition, however, prence of a cond EGFR mutation, the T790M substitution in exon 20, was discovered. The T790M is believed to be responsible for resistance to gefitinib therapy. Whether the subquent mutation was acquired de novo during the initially successful erlotinib therapy, or whether a small undetectable population of T790M cells was prent within the tumor tissue initially is unknown. Such a resistant clone could then lectively proliferate and become the major tumor cell population as the T790M-negative cells are eradicated by the therapy. Considering the general low frequency of the T790M mutation found in NSCLC patients prior to treatment, the de novo model appears more likely in the prented ca. The fact that the T790M cells also exhibited the original exon 19 mutation ems to indicate a common origin of all tumor cells,with a subpopulation acquiring the T790M resistant mutation.
It is clear that in order to further demonstrate the involvement of T790M, further patients would have to be screened prior, during and after the therapy. Experiments conducted on limited number of patients and cell lines published by other groups indicate that a ri of T790M,as well as other EGFR mutations,is linked to the therapy itlf, rather than clonal lection from the originally affected cell population. If confirmed, the detection of specific mutations may become uful for rational therapy lection as well as for monitoring of resistance during the therapy. This would include, in particular, patients with additional predictors, such as non-smokers with adenocarcinomas, with good quality of life and with disminated lung adenocarcinomas and bronchioloalveolar carcinomas.Acknowledgements
This work was supported by Internal Grant Agency of the Czech Ministry of Health, project no. NR/9087-3.
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湮远5 Pao W, Miller VA, Politi KA, Riely GJ et al:Acquired
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Received January 31, 2007
Revid March 29, 2007
蜂蜜什么样的好Accepted April 2, 2007
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