scholarly journals HIF-1 Inhibitor YC-1 Reverses the Acquired Resistance of EGFR-Mutant HCC827 Cell Line with MET Amplification to Gefitinib

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qian Jin ◽  
Jisheng Zheng ◽  
Ming Chen ◽  
Na Jiang ◽  
Xianrong Xu ◽  
...  
Keyword(s):  
Cell Line ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Hypoxia Inducible Factor ◽  
Growth Factor Receptor ◽  
Nonsmall Cell Lung Cancer ◽  
Met Amplification ◽  
Sensitivity Change ◽  
Pathway Inhibition ◽  
Egfr Mutant

Background. Acquired resistance occurred in the majority of nonsmall cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) therapy, and this may be related to the activation of the HIF-1 pathway. Therefore, we examined the influence of the hypoxia-inducible factor-1 (HIF-1) pathway inhibition on the sensitivity of HCC827 gefitinib-resistant (HCC827 GR) cells with MET amplification to gefitinib. Methods. We established HCC827 GR cell line with MET amplification and set four groups with different treatment. An MTT assay, a colony formation analysis, and a wound healing assay were performed to determine the sensitivity change of HCC827 GR cells after different treatments. HIF-1α, p-EGFR, and p-Met levels were detected with western blot. Correlations among HIF-1α, p-EGFR, and p-Met levels of HCC827 GR cells with different treatments were analyzed with Pearson’s correlation analysis. Results. HIF-1 inhibitor YC-1 enhanced the sensitivity of HCC827 GR cells to gefitinib. p-Met level was correlated with HIF-1α level, while there was no correlation between p-Met level and p-EGFR level. Conclusion. HIF-1 inhibitor YC-1 is able to reverse the acquired resistance of HCC827 GR to gefitinib, and the regulation of the HIF-1 pathway on MET may be one of the mechanisms.

scholarly journals The Journey of an EGFR-Mutant Lung Adenocarcinoma through Erlotinib, Osimertinib and ABCP Immunotherapy Regimens: Sensitivity and Resistance

2019 ◽  
Vol 12 (3) ◽  
pp. 765-776 ◽  
Author(s):  
Albina Kibirova ◽  
Malcolm D. Mattes ◽  
Matthew Smolkin ◽  
Patrick C. Ma
Keyword(s):  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Egfr Mutant ◽  
Egfr Tkis ◽  
Guided Therapy

Patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) have several EGFR targeting tyrosine kinase inhibitors (TKIs) available in frontline management. However, the disease will inevitably progress over time due to acquired resistance. Longitudinal tumor profiling for genomics guided therapy is indicated upon disease progression. It is a common scenario yet, when after failure of EGFR-TKIs, potentially actionable genomic alterations are lacking. Management of such patient is challenging with very limited options available. Combination of chemotherapy, anti-vascular/anti-angiogenic and immune-checkpoint inhibitors may become a salvage option for such patients. Here we describe a case of TKI refractory EGFR-mutant NSCLC successfully treated with carboplatin, paclitaxel, atezolizumab and bevacizumab combination with remarkable prompt tumor response.

scholarly journals Genomic Profiling Identifies Outcome-Relevant Mechanisms of Innate and Acquired Resistance to Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy in Lung Cancer

2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sebastian Michels ◽  
Carina Heydt ◽  
Bianca van Veggel ◽  
Barbara Deschler-Baier ◽  
Nuria Pardo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Third Generation ◽  
Met Amplification ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis

PURPOSE Third-generation epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) are effective in acquired resistance (AR) to early-generation EGFR TKIs in EGFR-mutant lung cancer. However, efficacy is marked by interindividual heterogeneity. We present the molecular profiles of pretreatment and post-treatment samples from patients treated with third-generation EGFR TKIs and their impact on treatment outcomes. METHODS Using the databases of two lung cancer networks and two lung cancer centers, we molecularly characterized 124 patients with EGFR p.T790M-positive AR to early-generation EGFR TKIs. In 56 patients, correlative analyses of third-generation EGFR TKI treatment outcomes and molecular characteristics were feasible. In addition, matched post-treatment biopsy samples were collected for 29 patients with progression to third-generation EGFR TKIs. RESULTS Co-occurring genetic aberrations were found in 74.4% of EGFR p.T790-positive samples (n = 124). Mutations in TP53 were the most frequent aberrations detected (44.5%; n = 53) and had no significant impact on third-generation EGFR TKI treatment. Mesenchymal-epithelial transition factor ( MET) amplifications were found in 5% of samples (n = 6) and reduced efficacy of third-generation EGFR TKIs significantly (eg, median progression-free survival, 1.0 months; 95% CI, 0.37 to 1.72 v 8.2 months; 95% CI, 1.69 to 14.77 months; P ≤ .001). Genetic changes in the 29 samples with AR to third-generation EGFR TKIs were found in EGFR (eg, p.T790M loss, acquisition of p.C797S or p.G724S) or in other genes (eg, MET amplification, KRAS mutations). CONCLUSION Additional genetic aberrations are frequent in EGFR-mutant lung cancer and may mediate innate and AR to third-generation EGFR TKIs. MET amplification was strongly associated with primary treatment failure and was a common mechanism of AR to third-generation EGFR TKIs. Thus, combining EGFR inhibitors with TKIs targeting common mechanisms of resistance may delay AR.

scholarly journals Distinct Characteristics and Clinical Outcomes to Predict the Emergence of MET Amplification in Patients with Non-Small Cell Lung Cancer Who Developed Resistance after Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3096
Author(s):  
Beung-Chul Ahn ◽  
Ji Hyun Lee ◽  
Min Hwan Kim ◽  
Kyoung-Ho Pyo ◽  
Choong-kun Lee ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Multivariate Logistic Regression ◽  
Small Cell Lung ◽  
Met Amplification ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

Objectives: Patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) ultimately acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) during treatment. In 5–22% of these patients, resistance is mediated by aberrant mesenchymal epithelial transition factor (MET) gene amplification. Here, we evaluated the emergence of MET amplification after EGFR-TKI treatment failure based on clinical parameters. Materials and Methods: We retrospectively analyzed 186 patients with advanced EGFR-mutant NSCLC for MET amplification status by in situ hybridization (ISH) assay after EGFR-TKI failure. We collected information including baseline patient characteristics, metastatic locations and generation, line, and progression-free survival (PFS) of EGFR-TKI used before MET evaluation. Multivariate logistic regression analysis was conducted to evaluate associations between MET amplification status and clinical variables. Results: Regarding baseline EGFR mutations, exon 19 deletion was predominant (57.5%), followed by L858R mutation (37.1%). The proportions of MET ISH assays performed after first/second-generation and third-generation TKI failure were 66.7% and 33.1%, respectively. The median PFS for the most recent EGFR-TKI treatment was shorter in MET amplification-positive patients than in MET amplification-negative patients (median PFS 7.0 vs. 10.4 months, p = 0.004). Multivariate logistic regression demonstrated that a history of smoking, short PFS on the most recent TKI, and less intracranial progression were associated with a high probability of MET amplification (all p < 0.05). Conclusions: Our results demonstrated the distinct clinical characteristics of patients with MET amplification-positive NSCLC after EGFR-TKI therapy. Our clinical prediction can aid physicians in selecting patients eligible for MET amplification screening and therapeutic targeting.

Monitoring of plasma pro-GRP level during EGFR-TKI treatment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10604-10604
Author(s):  
Yuko Kawano ◽  
Atsushi Horiike ◽  
Azusa Tanimoto ◽  
Toshio Sakatani ◽  
Ryota Saito ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Receptor Gene ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Patient Characteristics ◽  
T790m Mutation ◽  
Lung Cancers ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

10604 Background: Lung cancers harboring mutations in the epidermal growth factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but drug resistance invariably emerges. The major acquired mechanisms of resistance are the EGFR T790M mutation or MET gene amplification. Transformation from NSCLC into small-cell lung cancer (SCLC) has been recently identified in acquired resistance to EGFR-TKI. However, it is difficult to predict the transformation during EGFR-TKI treatment because obtaining serial and sufficient specimens for biopsy is difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels could predict SCLC transformation in resistance to EGFR-TKI. Methods: From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC who received EGFR-TKI treatment were enrolled. Plasma was obtained from these patients before EGFR-TKI treatment and when EGFR-TKI treatment failed. Pro-GRP and CEA levels were measured and compared before and after treatment. Results: Patient characteristics for 49 patients (15 men, 34 women) were as follows: median age, 62 years (41–81 years); histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 patients had received EGFR-TKI treatment (45 with gefitinib and 4 with erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the Pro-GRP levels had increased after treatment, but the CEA level did not increase. Objective responses to cytotoxic chemotherapy were noted in all 3 patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma Pro-GRP during EGFR-TKI treatment may be useful for early detection of SCLC transformation in resistance to EGFR-TKI.

Characterizing Acquired Resistance to TKIs in EGFR Mutant Lung Adenocarcinoma Cell Lines

2013 ◽  
Vol 9 ◽  
Author(s):  
Jing Sun
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Egfr Mutations ◽  
Mesenchymal Transition ◽  
Major Mechanism ◽  
Egfr Mutant

Traditional treatments for non-small cell lung adenocarcinomas do produce impressive improvements in patient health. Newly developed biologically based treatments exploit the drug-sensitivity conferred by mutations in the epidermal growth factor receptor (EGFR). In adenocarcinomas, cell proliferation and survival depend on mutant EGFR activity. For patients with certain EGFR mutations, treatment with tyrosine kinase inhibitors (TKIs) rather than chemotherapy improves patient survival. However, almost every patient acquires resistance to TKI treatment. About 50% of acquired resistance is because of a secondary mutation in EGFR. MET gene amplification, which allows cells to use MET to activate downstream signals, is another established mechanism. A third known mechanism is epithelial to mesenchymal transition (EMT). About 30% of all resistance mechanisms still remain unknown. This semester, the HCC2279 EGFR-mutant human adenocarcinoma line was characterized in hopes of discovering new models of resistance. Growth inhibition assays and immunoblotting were used to analyze the effects of treatments and to examine the status of signaling molecules. The HCC2279 resistant line appeared to have an EGFR-independent mechanism and did not seem to use MET as a major mechanism of resistance. The resistant cells continued to grow in the presence of TKI and TKI plus MET inhibitor, and immunoblotting showed that TKIs were capable of completely inhibiting the activation and phosphorylation of EGFR and MET. Signs of EMT were detected via immunoblotting due to a loss of E-cadherin and gain of vimentin, and EMT was corroborated by histological changes such as a loss in resistant cell polarity.

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