Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment

Rajappa, Senthil; Krishna, M. Vamshi; Parameswaran, Narayanan

doi:10.1007/s12325-019-00917-6

Cited by 17 publications

(8 citation statements)

References 63 publications

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“…About 50–60% resistant mechanism of the first generation EGFR TKIs was EGFR T790M gene mutation. Third-generation EGFR TKIs, such as osimertinib, alflutinib, target the T790M mutation with outstanding clinical efficacy ( 1 , 2 ).…”

Section: Introductionmentioning

confidence: 99%

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Wang

et al. 2021

Front. Oncol.

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PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

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Section: Introductionmentioning

confidence: 99%

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Wang

et al. 2021

Front. Oncol.

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“…Consequently, these results demonstrated that except for erlotinib-sensitive PC9 cells, FGFC1 could selectively inhibit the growth of erlotinib-resistant H1975 NSCLC cells, which harbors L858R/T790M double mutation of EGFR . Due to T790M might be the most important mutation, leading to the development of TKI resistance ( Rajappa et al, 2019 ), next we mainly evaluated the effects of FGFC1 on EGFR T790M mutant NSCLC cells.…”

Section: Resultsmentioning

confidence: 99%

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

et al. 2022

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Non-small cell lung cancer (NSCLC) is one of the most common malignancies in the world. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been used as a first-line treatment for patients harboring with EGFR mutations in advanced NSCLC. Nevertheless, the drug resistance after continuous and long-term chemotherapies considerably limits its clinical efficacy. Therefore, it is of great importance to develop new chemotherapeutic agents and treatment strategies to conquer the drug resistance. FGFC1 (Fungi fibrinolytic compound 1), a type of bisindole alkaloid from a metabolite of the rare marine fungi Starchbotrys longispora. FG216, has exhibited excellent fibrinolytic and anti-inflammatory activity. However, the potent efficacy of FGFC1 in human cancer therapy requires further study. Herein, we demonstrated that FGFC1 selectively suppressed the growth of NSCLC cells with EGFR mutation. Mechanistically, FGFC1 treatment significantly induced the apoptosis of erlotinib-resistant NSCLC cells H1975 in a dose-dependent manner, which was proved to be mediated by mitochondrial dysfunction and elevated accumulation of intracellular reactive oxygen species (ROS). Scavenging ROS not only alleviated FGFC1-induced apoptosis but also relieved the decrease of phospho-Akt. We further confirmed that FGFC1 significantly decreased the phosphorylation of protein EGFR, phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR) in H1975 cells. Notably, PI3K inhibitor (LY294002) could promote the accumulation of ROS and the expression levels of apoptosis-related proteins induced by FGFC1. Molecular dynamics simulations indicated that FGFC1 can inhibit EGFR and its downstream PI3K/Akt/mTOR pathway through directly binding to EGFR, which displayed a much higher binding affinity to EGFRT790M/L858R than EGFRWT. Additionally, FGFC1 treatment also inhibited the migration and invasion of H1975 cells. Finally, FGFC1 effectively inhibited tumor growth in the nude mice xenograft model of NSCLC. Taken together, our results indicate that FGFC1 may be a potential candidate for erlotinib-resistant NSCLC therapy.

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“…NSCLC has been reported in approximately four-fifths of patients with lung cancer [ 24 ]. This subtype has a poor prognosis with chemotherapy as first-line treatment [ 4 ], and 90% of NSCLC deaths are related to metastasis [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Baicalin Inhibits EMT through PDK1/AKT Signaling in Human Nonsmall Cell Lung Cancer

Chen

Yuan

Yang

et al. 2021

Journal of Oncology

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Background. Baicalin is a naturally occurring compound with anticancer, antioxidant, and anti-inflammatory properties. However, the mechanism underlying its anticancer activity on nonsmall cell lung cancer (NSCLC) remains unclear. Methods. The effects of baicalin on the progression and metastasis of experimental NSCLC cell lines were studied in vitro and in vivo. Wound-healing and transwell assays were performed to evaluate the potency of baicalin and the motility and migration ability of NCI-H460 cells. Immunofluorescence assay, western blot assay, and immunohistochemistry test were conducted to investigate the inhibiting effect of baicalin on the epithelial-mesenchymal transition (EMT) of NSCLC. Results. Baicalin inhibited the proliferation and migration of NCI-H446 human NSCLC cells in a dose-dependent manner, reduced the expression levels of phospho-3-phosphoinositide-dependent protein kinase 1 (p-PDK1) and phosphor-serine/threonine-protein kinase (p-AKT), reversed the levels of EMT markers, and inhibited the migration of NSCLC cells. Conclusions. Baicalin impedes EMT by inhibiting the PDK1/AKT pathway in human NSCLC and thus may be an effective alternative treatment for carcinoma and a new candidate antimetastasis drug.

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Integrating Osimertinib in Clinical Practice for Non-Small Cell Lung Cancer Treatment

Cited by 17 publications

References 63 publications

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs

FGFC1 Selectively Inhibits Erlotinib-Resistant Non-Small Cell Lung Cancer via Elevation of ROS Mediated by the EGFR/PI3K/Akt/mTOR Pathway

Baicalin Inhibits EMT through PDK1/AKT Signaling in Human Nonsmall Cell Lung Cancer

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