Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non-small cell lung cancer

Hsieh, Meng Heng; Fang, Yueh‐Fu; Chang, W.C.; Kuo, Han Pin; Lin, Shang-Hung; Liu, Hui Ping; Liu, Chih Lin; Chen, Hsiu Chi; Ku, Yuan; Chen, Ya Ting; Chang, Ya Hui; Chen, Ying-Tsong; Hsi, Bae‐Li; Tsai, Shih Feng; Huang, Shiu Feng

doi:10.1016/j.lungcan.2006.06.005

Cited by 70 publications

(49 citation statements)

References 38 publications

(135 reference statements)

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“…Complex EGFR mutations are more common in Asian lung cancer patients, including various forms of double mutations (13,14). 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.…”

Section: Discussionmentioning

confidence: 99%

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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%

“…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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“…However, variable responses to EGFR-targeting therapy, potentially raised from the diverse mutation patterns and genetic backgrounds in NSCLC patients, posed a challenge in selection of suitable patients (Hsieh et al, 2006). Resistance to EGFR-targeting agents resulted from a secondary T790M mutation is also an urgent issue to be addressed (Kobayashi et al, 2005;Kwak et al, 2005;Pao et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy

Yeh

Cheng

et al. 2007

Oncogene

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Mutations in epidermal growth factor receptor (EGFR) kinase domain associate with clinical responses to EGFR inhibitors and are frequently observed in non-small cell lung cancer (NSCLC) patients in East Asian populations. Clinically identified EGFR mutations cause constitutive receptor activation. The activating mechanisms were unclear but appeared to be different among EGFR mutants. We found that EGFR mutants had different sensitivity to an Src inhibitor PP2. S768I and L861Q mutants were less sensitive to Src suppression than others. Mutation at tyrosine 869 (845) residue, an Src phosphorylation site, decreased the phosphorylation levels of wild-type EGFR and other mutants, but not that of S768I and L861Q mutants, suggesting that S768I and L861Q mutants became Src independent for their activation and biological functions. In contrast, cells expressing EGFR-L858R or exon 19 deletion mutants were more sensitive to PP2 than cells expressing wild-type EGFR. Interestingly, EGFR with exon 19-deletion/T790M double mutations, which was resistant to gefitinib, remained sensitive to PP2. Taken together, our data indicate that Src inhibitors might be effective in treating NSCLC harboring specific types of EGFR mutations.

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“…10 Notably, the EGFR mutation incidence was only around 17À23% in Caucasians 10,11 and 40À60% in East Asians. 6,7,12 Therefore, identification of a novel biomarker other than EGFR mutation for predicting the efficacy of EGFR-TKIs will contribute to further individualizing NSCLC treatment.…”

Section: Introductionmentioning

confidence: 99%

Tumor‐associated macrophages correlate with response to epidermal growth factor receptor‐tyrosine kinase inhibitors in advanced non‐small cell lung cancer

Chung

Lee

Wang

et al. 2012

Intl Journal of Cancer

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Our study investigated whether tumor-associated macrophages (TAMs) in advanced non-small cell lung cancer (NSCLC) are related to treatment response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and may be a predictor of survival. Of 206 advanced NSCLC patients treated (first-line) with an EGFR-TKI at the study hospital from 2006 to 2009, 107 with adequate specimens for assessing CD68 immunohistochemistry as a marker of TAMs were assessed. After EGFR-TKI treatment, response was observed in 55 (51%) patients, and the median follow-up period was 13.5 months. Most TAMs were located in the tumor stroma (>95%) and positively costained with the M2 marker CD163. TAM counts were significantly higher in patients with progressive disease than in those without (p < 0.0001), a trend that remained in patients with known EGFR mutation status (n 5 59) and those with wild-type EGFR (n 5 20). High TAM counts, among other factors (e.g., wild-type EGFR), were significantly related to poor progression-free survival (PFS) and overall survival (OS) (all p < 0.0001 for TAMs). Multivariate Cox analyses showed that high TAM counts and EGFR mutations were both independent factors associated with PFS [odds ratio (OR), 8.0; 95% confidence interval (CI), 2.87-22.4; p 5 0.0001 and OR, 0.03; 95% CI, 0.003-0.31; p 5 0.003, respectively] and OS (OR, 2.641; 95% CI, 1.08-6.5; p 5 0.03 and OR, 0.14; 95% CI, 0.03-0.56; p 5 0.006, respectively). TAMs are related to treatment response irrespective of EGFR mutation and can independently predict survival in advanced NSCLC treated with an EGFR-TKI.

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Complex mutation patterns of epidermal growth factor receptor gene associated with variable responses to gefitinib treatment in patients with non-small cell lung cancer

Cited by 70 publications

References 38 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

EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy

Tumor‐associated macrophages correlate with response to epidermal growth factor receptor‐tyrosine kinase inhibitors in advanced non‐small cell lung cancer

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