A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

Russo, Alessandro; Franchina, Tindara; Ricciardi, Giuseppina Rosaria Rita; Picone, Antonio; Ferraro, Giuseppa; Zanghì, Mariangela; Toscano, Giuseppe; Giordano, Antonio; Adamo, Vincenzo

doi:10.18632/oncotarget.4254

Cited by 154 publications

(148 citation statements)

References 107 publications

(112 reference statements)

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“…There are four obstacles involved in the resistance to gefitinib that have recently been identified (16,17). The first is the activation of alternative tyrosine kinase receptors that bypass the EGFR pathway.…”

Section: Introductionmentioning

confidence: 99%

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

et al. 2017

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Abstract. Despite documentation of successful therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with lung cancer, the response rate of patients treated with this therapy remains low. The present study investigated whether L-ascorbic acid serves an adjuvant role in vitro when combined with the EGFR tyrosine kinase inhibitor gefitinib (Iressa ® ) in lung cancer cell lines. A total of three human lung cancer cell lines were used. The antiproliferative effects and changes in the cell cycle and expression of intracellular signaling molecules, including extracellular signal-regulated kinases (Erk), signal transducer and activator of transcription 3 (Stat3) and protein kinase B (Akt), were measured in cells treated with gefitinib and/or L-ascorbic acid at various concentrations. When combined with gefitinib, L-ascorbic acid exhibited an additive effect on cell proliferation in all gefitinib-sensitive and gefitinib-resistant cell lines. A decrement of ~40% was observed with a low dose 0.5 mM L-ascorbic acid and gefitinib in the relatively gefitinib-resistant A549 cell line (85.6±5.4% with gefitinib alone vs. 52.7±7.3% with combination therapy; P=0.046). The downregulation of intracellular signaling cascades, including EGFR, Akt, Erk and Stat3, was also observed. L-Ascorbic acid serves an adjuvant role when administered in combination with gefitinib; however, the degree of inhibition of cell proliferation differs between lung cancer cell lines.

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Section: Introductionmentioning

confidence: 99%

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

et al. 2017

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“…This discrepancy may be explained by relatively few early-stage samples being analyzed in the present cohort. Lung cancer tissues exhibiting EGFR mutations have demonstrated success in responding to EGFR tyrosine kinase inhibitors (26,27). An equal distribution of EGFR mutations in exon 19 (5/28) and the L858R point mutation in exon 21 (5/28) were identified in the present study, followed by the p.G719A point mutation in exon 8 (1/28).…”

Section: Discussionmentioning

confidence: 99%

Targeted sequencing reveals distinct pathogenic variants in Chinese patients with lung adenocarcinoma brain metastases

Chen

Yang³

et al. 2018

Oncol Lett

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Abstract. Lung cancer is the most common type of malignancy to metastasize to the brain, with the median survival time of patients being 6-11 months. In the present study, the aim was to compare the actionable gene mutation profiles of primary lung adenocarcinoma (LC) samples and LC brain metastasis (LCBM) samples through targeted sequencing. Next generation sequencing (NGS) of 13 formalin-fixed, paraffin-embedded LC samples and 15 LCBM samples was performed using a customized OncoAim™ cancer panel and OncoAim™ RNA fusion panel on the MiSeq platform. The OncoAim™ cancer panel pipeline and OncoAim™ RNA fusion panel pipeline were used for bioinformatic analysis. Together, 43 variants were observed in 7 genes from the 28 cancer samples. The mutated genes of LCBM were tumor protein (TP)53, epidermal growth factor receptor (EGFR), catenin β1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, mothers against decapentaplegic homolog 4, Kirsten rat sarcoma viral oncogene homolog (KRAS) and proto-oncogene B-Raf, which were exhibited in 10/15 (66.7%), 6/15 (40.0%), 3/15 (20.0%), 2/15 (13.3%), 2/15 (13.3%), 1/15 (6.7%) and 1/15 (6.7%) of samples, respectively. The mutated genes of LC were TP53, EGFR and KRAS, which were exhibited in 11/13 (84.6%), 5/13 (38.5%) and 2/13 (18.2%) of samples, respectively. echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase rearrangements were present in 1 LCBM sample. For 2 LC samples and 1 LCBM sample, no genetic alterations were observed. The NGS data also revealed a novel 4-codon deletion of TP53 (p.V166_H169del) and a novel TP53 splice site mutation (7577157-63del TACTCAG). Further potentially actionable mutations were detected in LCBM, indicating a high degree of genetic heterogeneity between the LC and LCBM samples that were analyzed. The present study demonstrated that NGS provides an improved approach for the discovery of potentially actionable mutations and the understanding of the mechanisms underlying tumor progression and evolution.

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“…Based on the in vitro dissolution test, NUFS-Ert was predicted to show markedly higher BA than Tarceva V R in fasted beagle dogs, which would result in a lower variation in BA in fasted and fed conditions. The BA of Tarceva V R was reported to be about 60% in the fasted condition; however, it may increase up to 100% when taken with food [12,30]. Thus, the variation in the BA of Tarceva V R in the fasted and fed conditions, which was about 5.8 times in beagle dogs, would be about 1.6 times in humans (100%: 60%).…”

Section: Discussionmentioning

confidence: 99%

Nanoparticulation improves bioavailability of Erlotinib

Yang

Shin

Park

et al. 2017

Drug Development and Industrial Pharmacy

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Objectives: Nanoparticulation using fat and supercritical fluid (NUFS TM ) is a drug delivery platform technology enabling efficient and effective formulation of poorly soluble drugs. We performed experiments to examine whether NUFS TM could improve poor bioavailability and reduce fed-fasted bioavailability variances of erlotinib (Ert). Methods: NUFS-Ert was prepared using NUFS TM technology; its physical properties were characterized, and drug release was measured. Furthermore, in vitro and in vivo efficacy tests and pharmacokinetic analysis were performed. Results: NUFS-Ert nanoparticles had an average size of 250 nm and were stable for 2 months at 40 C, 4 C, and room temperature. The dissolution rate of NUFS-Ert increased in bio-relevant dissolution media. NUFS-Ert was more potent in inhibiting EGF signaling and in suppressing the proliferation of A549, a human non-small cell lung cancer cell line. Furthermore, A549 xenografts in BALB/c nude mice treated with NUFS-Ert regressed more efficiently than those in the mice treated with vehicle or Tarceva V R . In addition, experimental lung metastasis was more efficiently inhibited by NUFS-Ert than by Tarceva V R . The relative bioavailability of NUFS-Ert compared with that of Tarceva V R was 550% and the ratio of the area under the concentration-time curve (AUC) of fed state to the AUC of fasted state was 1.8 for NUFS-Ert and 5.8 for Tarceva V R . Conclusions: NUFS-Ert could improve poor bioavailability and reduce fed-fasted bioavailability variances of Ert. NUFS-Ert was more efficacious than Tarceva V R .ARTICLE HISTORY

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A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

Cited by 154 publications

References 107 publications

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

The enhanced tumor inhibitory effects of gefitinib and L-ascorbic acid combination therapy in non-small cell lung cancer cells

Targeted sequencing reveals distinct pathogenic variants in Chinese patients with lung adenocarcinoma brain metastases

Nanoparticulation improves bioavailability of Erlotinib

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