Presence of<i>Epidermal Growth Factor Receptor</i>Gene T790M Mutation as a Minor Clone in Non–Small Cell Lung Cancer

Inukai, Michio; Toyooka, Shinichi; Ito, Sachio; Asano, Hiroaki; Ichihara, Shuji; Soh, Junichi; Suehisa, Hiroshi; Ouchida, Mamoru; Aoe, Keisuke; Aoe, Motoi; Kiura, Katsuyuki; Shimizu, Nobuyoshi; Date, Hiroshi

doi:10.1158/0008-5472.can-06-1951

Cited by 400 publications

(283 citation statements)

References 20 publications

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“…The reported double mutations (13)(14)(15)(16)(17)(18) generally involve a common activating mutation such as L858R and a rare mutation such as T790M. Concomitant T790M and L858R mutations confer gefitinib resistance in NSCLC patients (17,18).…”

Section: Discussionmentioning

confidence: 99%

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Tam

Leung

Tin

et al. 2009

Molecular Cancer Therapeutics

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Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas, especially from nonsmoking women of Asian descent. We have previously shown EGFR mutations occur in >70% of lung adenocarcinoma from nonsmokers in our population with a complex mutational profile, including 13% of EGFR double mutations. In this study, we investigated the in vitro gefitinib response of four EGFR double mutants identified in untreated patients, including Q787R+L858R, E709A+G719C, T790M+L858R, and H870R+L858R. The phosphorylation profiles of EGFR and downstream effectors AKT, STAT3/5, and ERK1/2 were compared by immunoblot analyses among the single and double mutants transfected into H358 cells. Results showed that mutants responded to in vitro gefitinib treatment with different sensitivities. The G719C and L858R single mutants showed the highest gefitinib sensitivity compared with the corresponding coexisting single mutants E709A, Q787R, H870R, and T790M. The double mutants E709A+G719C, Q787R+L858R, and H870R+L858R showed attenuated responses to gefitinib in the EGFR and downstream effector phosphorylation profiles compared with G719C or L858R alone. T790M+L858R showed strong resistance to gefitinib. Clinically, the patient whose tumor contained H870R+L858R showed tumor stabilization by 250 mg oral gefitinib daily but cerebral metastasis developed 6 months later. Correlation with the in vitro phosphorylation profile of H870R +L858R suggested that treatment failure was probably due to inadequate suppression of EGFR signaling by the drug level attainable in the cerebrospinal fluid at the given oral dosage. Overall, the findings suggested that rare types of EGFR substitution mutations could confer relative gefitinib resistance when combined with the common activating mutants. [Mol Cancer Ther

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Section: Discussionmentioning

confidence: 99%

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Tam

Leung

Tin

et al. 2009

Molecular Cancer Therapeutics

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“…In fact, direct sequencing could fail to detect mutated subclones (Pao and Ladanyi, 2007). Some EGFR-mutated subclones were already detected in NSCLC when EGFR T790M mutations have been analysed with sensitive techniques (Inukai et al, 2006). It was suggested that the possible presence of such mutations at a low frequency in NSCLC tumours before EGFRtargeted therapy might affect the tumour response or the eventfree survival after targeted treatments.…”

Section: Discussionmentioning

confidence: 99%

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping

et al. 2009

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Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P <0.005), among which five in samples with low tumour cellularity. In adenocarcinoma, K-Ras mutation frequency increased from 7 out of 55 (13%) by direct sequencing to 15 out of 55 (27%) by clamped-PCR ( P <0.005). K-Ras mutations detected by these sensitive techniques lost its prognostic value. In conclusion, a rapid and sensitive PCR-clamping test avoiding macro or micro dissection could be proposed in routine analysis especially for NSCLC samples with low percentage of tumour cells such as bronchial biopsies or after neoadjuvant chemotherapy.

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“…In tumours from patients not treated with TKI, T790M appears to be rare, approximately 0.5% . The possibility exists, however, that this second mutation might be present at a low frequency at the time of diagnosis and that tumour cells harbouring this mutation might be enriched over time during treatment with gefitinib (Inukai et al, 2006).…”

Section: Resistance To Egfr-tkimentioning

confidence: 99%

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

Uramoto

Mitsudomi

2007

Br J Cancer

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Subsets of patients with non-small cell lung cancer respond remarkably well to small molecule tyrosine kinase inhibitors (TKI) specific for epidermal growth factor receptor (EGFR) such as gefitinib or erlotinib. In 2004, it was found that EGFR mutations occurring in the kinase domain are strongly associated with EGFR-TKI sensitivity. However, subsequent studies revealed that this relationship was not perfect and various predictive markers have been reported. These include EGFR gene copy numbers, status of ligands for EGFR, changes in other HER family genes or molecules downstream to EGFR including KRAS or AKT. In this review, we would like to review current knowledge of predictive factors for EGFR-TKI. As all but one phase III trials failed to show a survival advantage of the treatment arm involving EGFR-TKIs, it is necessary to select patients by these biomarkers in future clinical trials. Through these efforts, it would be possible to individualise EGFR-TKI treatment for patients suffering from lung cancer.

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Presence ofEpidermal Growth Factor ReceptorGene T790M Mutation as a Minor Clone in Non–Small Cell Lung Cancer

Cited by 400 publications

References 20 publications

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Double EGFR mutants containing rare EGFR mutant types show reduced in vitro response to gefitinib compared with common activating missense mutations

Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping

Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer?

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