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Efficacy of chemotherapy plus gefitinib treatment in advanced non-small-cell lung cancer patients following acquired resistance to gefitinib.

ABSTRACT: Non-small-cell lung cancer (NSCLC) may exhibit oncogene addiction in patients who benefited from prior treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Preclinical data suggested that EGFR addiction persists after the development of TKI resistance, leading many clinicians to continue TKI treatment along with chemotherapy. However, this strategy has not been adequately evaluated in clinical practice. Patients who benefited from gefitinib followed by acquired resistance to this drug were reviewed in the Zhejiang Cancer Hospital. Patients were included if they received chemotherapy and gefitinib following failure of prior gefitinib treatment. A total of 26 patients were included in the present study. Six patients (23.1%) exhibited a partial response (PR), 13 (50%) achieved stable disease (SD) and 7 (26.9%) had progressive disease (PD) during the chemotherapy and gefitinib treatment. The disease control rate (DCR) was 73.1% and the median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI): 3.8-5.4]. The toxicities associated with gefitinib and chemotherapy were generally acceptable. In conclusion, continued concurrent gefitinib and chemotherapy may be a valuable strategy, with acceptable and well-tolerated toxicity. However, this treatment requires further investigation.

SUBMITTER: Song Z

PROVIDER: S-EPMC3915312 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Efficacy of chemotherapy plus gefitinib treatment in advanced non-small-cell lung cancer patients following acquired resistance to gefitinib.

Song Zhengbo Z Zhang Yiping Y

Molecular and clinical oncology 20130723 5

Non-small-cell lung cancer (NSCLC) may exhibit oncogene addiction in patients who benefited from prior treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Preclinical data suggested that EGFR addiction persists after the development of TKI resistance, leading many clinicians to continue TKI treatment along with chemotherapy. However, this strategy has not been adequately evaluated in clinical practice. Patients who benefited from gefitinib followed by acquir ...[more]

PMID: 24649264

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Project description:Background: Gefitinib is a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used to treat EGFR mutation-positive patients with non-small cell lung cancer (NSCLC). However, the efficacy of gefitinib is limited by the development of acquired resistance. Studies have shown that circular RNAs (circRNAs) are involved in the acquired resistance to many anticancer agents. However, the expression profiles and functions of circRNAs in gefitinib resistance in NSCLC are poorly understood so far. Methods: In this study, circRNA expression profiling was explored in two gefitinib-resistant NSCLC cell lines (HCC827/GR and PC9/GR) and their parental sensitive cells (HCC827 and PC9) using high-throughput RNA sequencing. Quantitative real-time PCR (qRT-PCR) was used to confirm the expression of selected differentially expressed circRNAs. Bioinformatic tools including gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), network analysis, and Kaplan-Meier plotter database were used to predict the functions and pathways of these differentially expressed circRNAs. Results: We identified 46 and 56 differentially expressed circRNAs in HCC827/GR and PC9/GR cell lines, respectively, compared with those in their parental cell lines. Gene ontology and KEGG pathway analysis identified that the host linear transcripts of these differentially expressed circRNAs were involved in many critical biological pathways and molecular functions. We found that hsa_circ_0000567 was consistently up-regulated, and hsa_circ_0006867 was consistently down-regulated in two resistant cell lines. We further used hsa_circ_0000567 and hsa_circ_0006867 as key circRNAs to construct circRNA-miRNA-mRNA networks. Several target mRNAs of these two circRNAs had been shown to significantly associate with the overall survival of patients with lung cancer. Conclusions: In this study, we generated the comprehensive expression and functional profiles of the differentially expressed circRNAs between gefitinib-resistant and -sensitive NSCLC cells, and showed that dysregulation of circRNAs might play an important role in the development of acquired resistance to gefitinib in NSCLC.

Project description:Most gefitinib-treated patients with non-small cell lung cancer (NSCLC) would eventually develop resistance. Lysimachia capillipes (LC) capilliposide extracts from LC Hemsl. show both in vitro and in vivo anti-cancer effects. In this study we investigated whether LC capilliposide in combination with gefitinib could overcome the resistance of NSCLC cells to gefitinib and identified the signaling pathways involved. Treatment with LC capilliposide alone inhibited the growth of a panel of NSCLC cell lines (PC-9, H460, H1975, H1299 and PC-9-GR) sensitive or resistant to gefitinib with IC50 values in the range of μg/mL. In the gefitinib-resistant PC-9-GR cells (which have a T790M EGFR mutation), LC capilliposide (at the IC30, i.e.1.2 μg/mL) markedly enhanced the inhibitory effects of gefitinib with its IC50 value being decreased from 6.80±1.00 to 0.77±0.12 μmol/L. By using the median effect analysis we showed that combination treatment of LC capilliposide and gefitinib could restore gefitinib sensitivity in PC-9-GR cells. Furthermore, LC capilliposide (1.2 μg/mL) significantly increased the apoptotic responses to gefitinib (0.77 μmol/L) in PC-9-GR cells, but did not affect gefitinib-induced G0/G1 arrest. Moreover, LC capilliposide (1.2 μg/mL) in combination with gefitinib (0.77, 1.0 μmol/L) markedly decreased the phosphorylation of the EGFR downstream signaling molecule AKT, which neither LC capilliposide nor gefitinib alone affected. In PC-9-GR cells with siRNA knockdown of AKT, addition of LC capilliposide was unable to increase gefitinib sensitivity. In a PC-9-GR xenograft mouse model, combination treatment with LC capilliposide (15 mg·kg-1·d-1, ip) and gefitinib (50 mg·kg-1·d-1, ip) dramatically enhanced tumor growth suppression (with a TGI of 109.3%), compared with TGIs of 22.6% and 56.6%, respectively, in mice were treated with LC capilliposide or gefitinib alone. LC capilliposide can restore the cells' sensitivity to gefitinib through modulation of pAKT levels, suggesting that a combination of LC capilliposide and gefitinib may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLCs with a T790M mutation.

Project description:BackgroundWhether a combination of chemotherapy and erlotinib is beneficial for advanced non-small cell lung cancer (NSCLC) remains controversial. This study aimed to summarize the currently available evidence and compare the efficacy and safety of chemotherapy plus erlotinib versus chemotherapy alone for treating advanced NSCLC.MethodsEMBASE, PubMed, and the Cochrane Central Register of Controlled Trials were searched for relevant studies. Our protocol was registered in PROSPERO (CRD42014015015).ResultsNine randomized controlled trials with a total of 3599 patients were included. Compared to chemotherapy alone, chemotherapy plus erlotinib was superior in PFS (HR = 0.76 [95% CI 0.62, 0.92], P = 0.006), and no statistically significant difference was observed in OS (HR = 0.94 [95% CI 0.86, 1.03], P = 0.16). Intercalated erlotinib plus chemotherapy demonstrated improvements in PFS (HR = 0.67 [95% CI 0.50, 0.91], P = 0.009) and OS (HR = 0.82 [95% CI 0.69, 0.98], P = 0.03). Continuous erlotinib plus chemotherapy treatment failed to demonstrate improvements in PFS (HR = 0.91 [95% CI 0.80, 1.04], P = 0.16) and OS (HR = 0.98 [95% CI 0.89, 1.09], P = 0.75). The association of chemotherapy plus erlotinib with improvement in PFS was significant in never smoking patients (HR = 0.46 [95% CI 0.37, 0.56], P<0.00001) but not in smoking patients (HR = 0.70 [95% CI 0.49, 1.00], P = 0.05). Among patients with EGFR mutant tumors, chemotherapy plus erlotinib demonstrated significant improvements in PFS (HR = 0.31 [95% CI 0.17, 0.58], P = 0.0002) and OS (HR = 0.52 [95% CI 0.30, 0.88], P = 0.01). Among patients with EGFR wild-type tumors, no statistically significant difference was observed with respect to PFS (HR = 0.87 [95% CI 0.70, 1.08], P = 0.21) and OS (HR = 0.78 [95% CI 0.59, 1.01], P = 0.06).ConclusionCombination of chemotherapy and erlotinib is a viable treatment option for patients with NSCLC, especially for patients who never smoked and patients with EGFR mutation-positive disease. In addition, intercalated administration is an effective combinatorial strategy.

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Efficacy of chemotherapy plus gefitinib treatment in advanced non-small-cell lung cancer patients following acquired resistance to gefitinib.

Publications

Efficacy of chemotherapy plus gefitinib treatment in advanced non-small-cell lung cancer patients following acquired resistance to gefitinib.

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