Osimertinib Resistance With a Novel EGFR L858R/A859S/Y891D Triple Mutation in a Patient With Non-Small Cell Lung Cancer: A Case Report

Targeted drug therapy based on the types of epidermal growth factor receptor (EGFR) gene mutations has been widely used in the diagnosis and treatment of patients with non-small cell lung cancer (NSCLC). With the development of next-generation sequencing (NGS) technology, more and more EGFR-tyrosine kinase inhibitor (TKI) resistance mutation sites have been revealed. Here, we report a novel EGFR L858R/A859S/Y891D triple mutation in plasma-derived circulating tumor DNA (ctDNA) was identified in a 53-year-old male patient with NSCLC resistant to osimertinib treatment, using an ultra-deep (20,000×) 160-gene panel through the NGS platform. Our case confirms that dynamic monitoring of liquid biopsy based on ctDNA is conducive to the selection of targeted therapy and the realization of the patient’s full course management.

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MicroRNA-200a Targets EGFR and c-Met to Inhibit Migration, Invasion, and Gefitinib Resistance in Non-Small Cell Lung Cancer

Cytogenetic and Genome Research ◽

10.1159/000434741 ◽

2015 ◽

Vol 146 (1) ◽

pp. 1-8 ◽

Cited By ~ 35

Author(s):

Qiang Zhen ◽

Junfeng Liu ◽

Lina Gao ◽

Jiabao Liu ◽

Renfeng Wang ◽

...

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Tyrosine Kinases ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Small Cell ◽

Migration And Invasion ◽

Small Cell Lung

Lung cancer, especially non-small cell lung cancer (NSCLC), is the major cause of cancer death worldwide. Mutations in epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), both of which are receptor tyrosine kinases, have been identified in a considerable percentage of NSCLC patients. EGFR and c-Met share the same downstream pathways and cooperate not only in promoting metastasis but also in conferring resistance to tyrosine kinase inhibitor (TKI) therapies in NSCLC. MicroRNAs (miRNAs) are a family of small non-coding RNAs, usually 21-25 nucleotides long, and are critical in regulating gene expression. Abnormal miRNA expression has been implicated in the initiation and progression in many forms of cancers, including lung cancer. In this study, we found that miR-200a is downregulated in NSCLC cells, where it directly targets the 3′-UTR of both EGFR and c-Met mRNA. Overexpression of miR-200a in NSCLC cells significantly downregulates both EGFR and c-Met levels and severely inhibits cell migration and invasion. Moreover, in NSCLC cell lines that are resistant to gefitinib, a drug often used in TKI therapies to treat NSCLC, miR-200a expression is able to render the cells much more sensitive to the drug treatment.

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Synergistic Anticancer Effects of Curcumin and Hinokitiol on Gefitinib Resistant Non-Small Cell Lung Cancer Cells

Natural Product Communications ◽

10.1177/1934578x1801301223 ◽

2018 ◽

Vol 13 (12) ◽

pp. 1934578X1801301 ◽

Cited By ~ 1

Author(s):

Tae-Bok Lee ◽

Eun-Ju Seo ◽

Ji-Yun Lee ◽

Jin Hyun Jun

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cancer Cells ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Small Cell ◽

Small Cell Lung ◽

Anticancer Effects ◽

Gefitinib Resistance

This study evaluated the synergistic effect of curcumin (diferuloylmethane) and hinokitiol (β-thujaplicin), natural product derived phytochemicals, on gefitinib (Iressa) resistant non-small cell lung cancer (NSCLC) cells. Gefitinib, a tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR), is widely used for lung cancer treatment. However, gefitinib resistance is easily acquired by NSCLC and followed by the development of progressive disease. Curcumin and hinokitiol are well-known bioactive compounds demonstrating anti-inflammation, anti-bacteria and anticancer effects. However, the effects of co-treatment of curcumin and hinokitiol on cancer cells have not been reported. Here, we postulated, for the first time, the possibility of combination therapy with curcumin and hinokitiol for treatment of gefitinib resistant NSCLC via increment of apoptosis and lysosomal enlargement.

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Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s7340 ◽

2012 ◽

Vol 6 ◽

pp. CMO.S7340 ◽

Cited By ~ 16

Author(s):

Takuya Araki ◽

Hideaki Yashima ◽

Kimihiro Shimizu ◽

Tohru Aomori ◽

Tadahiro Hashita ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Drug Effects ◽

Small Cell ◽

Small Cell Lung ◽

Gefitinib Treatment

In the past decade, molecular-targeted drugs have been focused upon for the treatment of cancer. In 2002, gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor became available in Japan for the treatment of non-small cell lung cancer (NSCLC). Over 80% of selected patients, such as EGFR mutation-positive patients, respond to gefitinib treatment; however, most patients develop acquired resistance to gefitinib within a few years. Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects. This article reviews the use of gefitinib for the treatment of NSCLC from a pharmaceutical viewpoint.

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Bioinformatic identification of the potential afatinib drug resistance gene BIRC5 in non-small- cell lung cancer

10.21203/rs.3.rs-396954/v1 ◽

2021 ◽

Author(s):

Xiaoxi Zhu ◽

Yuanzhi Lu ◽

Qiang Chen ◽

Yin Li

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Small Cell Lung Cancer ◽

Candidate Gene ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Small Cell ◽

Potential Candidate ◽

Small Cell Lung

Abstract Background Drug resistance inevitably limits the efficacy of the second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) afatinib, and the underlying causes of this resistance have not been determined.Methods In this study, we demonstrated that baculovirus IAP repeat protein 5 (BIRC5) may confer afatinib resistance in non-small-cell lung cancer (NSCLC) via multiple mechanisms based on integrative bioinformatic analyses. Results Through bioinformatic analyses of microarray datasets, BIRC5 was overexpressed in both afatinib-resistant NSCLC cells and NSCLC tissues and was initially identified as a potential candidate gene causing poor survival in afatinib-resistant patients with NSCLC. The resistance function of BIRC5 in NSCLC was validated by performing protein/gene interactions and biological process annotation analyses and further validated by analyzing transcription factors targeting BIRC5 mRNA. Conclusions We applied our results to NSCLC and showed that BIRC5 was an important candidate gene for afatinib resistance.

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Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non–Small-Cell Lung Cancer

JCO Precision Oncology ◽

10.1200/po.20.00279 ◽

2021 ◽

pp. 177-190

Author(s):

Caroline E. McCoach ◽

Aiming Yu ◽

David R. Gandara ◽

Jonathan W. Riess ◽

Daniel P. Vang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Dose Escalation ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Small Cell ◽

Small Cell Lung ◽

Specific Patient ◽

Egfr Mutant

PURPOSE MET dysregulation is an oncogenic driver in non–small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor ( EGFR)–mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance. METHODS A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination. RESULTS The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%. CONCLUSION Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.

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Kanglaite Combined With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapy for Stage III/IV Non-Small Cell Lung Cancer: A PRISMA-Compliant Meta-Analysis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.739843 ◽

2021 ◽

Vol 12 ◽

Author(s):

Fanming Kong ◽

Chaoran Wang ◽

Xiaojiang Li ◽

Yingjie Jia

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Small Cell ◽

Stage Iii ◽

Small Cell Lung ◽

Epidermal Growth ◽

Egfr Tki

Objective: Kanglaite(KLT), a type of Chinese medicine preparation, is considered as an adjuvant therapeutic option for malignant cancer treatment. This study aimed to systematically investigate the efficacy and safety of the combination of KLT and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for the treatment of stage III/IV non-small cell lung cancer.Methods: Randomized controlled trials (RCTs) that compared KLT plus EGFR-TKI with EGFR-TKI alone for the treatment of stage III/IV non-small cell lung cancer were reviewed. Literature searches (up to July 10, 2021) were performed on PubMed, Web of Science, Cochrane Library, Embase, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), Wanfang Database, and the Chinese Scientific Journal Database. Two researchers independently assessed the risk of bias with the tool of Cochrane Collaboration. RevMan 5.3.0 was used in the analysis of the included trial data.Results: 12 RCTs recruiting 1,046 patients with stage III/IV NSCLC were included. Results showed that compared with EGFR-TKI alone, KLT plus EGFR-TKI significantly increased the disease control rate (DCR) (odds ratio [OR]=3.26; 95% confidence interval [CI]:2.22–4.77; p < 0.00001), the objective response rate (ORR) (OR=2.59; 95% CI:1.87–3.58; p < 0.00001) and Karnofsky performance status (KPS) (OR = 2.76; 95% CI:1.73–4.39; p < 0.00001). Furthermore, patient immunity was enhanced with KLT plus EGFR-TKI. The combined treatment increased the percentage of CD4 + T cells (weighted mean difference [WMD]=5.36; 95% CI:3.60–7.13; p < 0.00001),the CD4+/CD8 + ratio (WMD = 0.18; 95% CI: 0.08–0.27; p = 0.004), and percentage of NK cells (WMD=4.84; 95% CI: 3.66–6.02; p < 0.00001).With regard to drug toxicity, the occurrence rate of nausea and vomiting was significantly reduced by KLT plus EGFR-TKI (OR=0.37; 95% CI: 0.16–0.86; p = 0.02).Conclusion: KLT plus EGFR-TKI was effective in treating stage III/IV non-small cell lung cancer. Thus, its application in these patients is worth promoting. Additional double-blind, well-designed and multicenter RCTs are required to confirm the efficacy and safety of this treatment.

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P84.20 VATS Right Upper Lobectomy for Advanced Non-Small Cell Lung Cancer After ALK-Tyrosine Kinase Inhibitor Administration.

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.1219 ◽

2021 ◽

Vol 16 (3) ◽

pp. S666-S667

Author(s):

K. Yamamoto ◽

M. Kuwahara ◽

S. Yamamoto

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitor ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Small Cell ◽

Small Cell Lung

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Phase II, Multicenter, Uncontrolled Trial of Single-Agent Sorafenib in Patients With Relapsed or Refractory, Advanced Non–Small-Cell Lung Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.22.0541 ◽

2009 ◽

Vol 27 (26) ◽

pp. 4274-4280 ◽

Cited By ~ 144

Author(s):

George R. Blumenschein ◽

Ulrich Gatzemeier ◽

Frank Fossella ◽

David J. Stewart ◽

Lisa Cupit ◽

...

Keyword(s):

Lung Cancer ◽

Growth Factor ◽

Small Cell Lung Cancer ◽

Phase Ii ◽

Cell Lung Cancer ◽

Advanced Nsclc ◽

Growth Factor Receptor ◽

Small Cell ◽

Continuous Treatment ◽

Small Cell Lung

PurposeSorafenib is an oral multikinase inhibitor that targets the Ras/Raf/MEK/ERK mitogenic signaling pathway and the angiogenic receptor tyrosine kinases, vascular endothelial growth factor receptor 2 and platelet-derived growth factor receptor β. We evaluated the antitumor response and tolerability of sorafenib in patients with relapsed or refractory, advanced non–small-cell lung cancer (NSCLC), most of whom had received prior platinum-based chemotherapy.Patients and MethodsThis was a phase II, single-arm, multicenter study. Patients with relapsed or refractory advanced NSCLC received sorafenib 400 mg orally twice daily until tumor progression or an unacceptable drug-related toxicity occurred. The primary objective was to measure response rate.ResultsOf 54 patients enrolled, 52 received sorafenib. The predominant histologies were adenocarcinoma (54%) and squamous cell carcinoma (31%). No complete or partial responses were observed. Stable disease (SD) was achieved in 30 (59%) of the 51 patients who were evaluable for efficacy. Four patients with SD developed tumor cavitation. Median progression-free survival (PFS) was 2.7 months, and median overall survival was 6.7 months. Patients with SD had a median PFS of 5.5 months. Major grades 3 to 4, treatment-related toxicities included hand-foot skin reaction (10%), hypertension (4%), fatigue (2%), and diarrhea (2%). Nine patients died within a 30-day period after discontinuing sorafenib, and one patient experienced pulmonary hemorrhage that was considered drug related.ConclusionContinuous treatment with sorafenib 400 mg twice daily was associated with disease stabilization in patients with advanced NSCLC. The broad activity of sorafenib and its acceptable toxicity profile suggest that additional investigation of sorafenib as therapy for patients with NSCLC is warranted.

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