scholarly journals T790M mutation in stage IV EGFR-mutated NSCLC patient with acquired resistance reverted to original 19Del mutation after administration of a series of precision treatments: a case report

2018 ◽  
Vol 1 (3) ◽  
pp. 129-133 ◽  
Author(s):  
Jialong Han ◽  
Ya Wang ◽  
Lili Zhong ◽  
Huijie Zhou ◽  
Min Yu ◽  
...  
Keyword(s):  
Case Report ◽  
Nsclc Patient ◽  
Acquired Resistance ◽  
Stage Iv ◽  
T790m Mutation ◽  
Egfr Mutated

Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment: Is there a rationale for a clinical trial?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19099-e19099
Author(s):  
Nello Salesi ◽  
Barbara Di Cocco ◽  
Francesca Calabretta ◽  
Alida Armida Ciorra ◽  
Crescenzo Cirino ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Biologically Active ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Free Survival ◽  
Tki Resistance ◽  
Egfr Mutated

e19099 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated pts resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Methods: Retrospective review of 5 EGFR mutated (exon 19 deletions) patients that were given gefitinib and subsequently erlotinib. Results: All pts responded to gefitinib with median progression-free survival of 13 months (95% confidence interval, 4-16). After gefitinib resistance, 60% (3 of 5) of these pts displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). These pts acquired the T790M mutation. 2 gefitinib-resistant pts with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. In literature doesn’t exist a prospective study about the stratification of pts ordered by PS, age, gender, smoker/non-smoker, which could test the efficiency of the erlotinib after gefitinib in pts with different EGFR mutations. We only have at our disposal few studies control-case in non-selected pts which show a potential efficiency of erlotinib after the failure of the gefitinib, nevertheless, without an evident increase of the overall survival. Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most pts. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.

scholarly journals Mechanism of Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors and a Potential Treatment Strategy

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 212 ◽  
Author(s):  
Tatsuya Nagano ◽  
Motoko Tachihara ◽  
Yoshihiro Nishimura
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
T790m Mutation ◽  
Epidermal Growth ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr Tkis

Treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) improves the overall survival of patients with EGFR-mutated non-small-cell lung cancer (NSCLC). First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) or second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) are effective for the treatment of EGFR-mutated NSCLC, especially in patients with EGFR exon 19 deletions or an exon 21 L858R mutation. However, almost all cases experience disease recurrence after 1 to 2 years due to acquired resistance. The EGFR T790M mutation in exon 20 is the most frequent alteration associated with the development of acquired resistance. Osimertinib—a third-generation EGFR-TKI—targets the T790M mutation and has demonstrated high efficacy against EGFR-mutated lung cancer. However, the development of acquired resistance to third-generation EGFR-TKI, involving the cysteine residue at codon 797 mutation, has been observed. Other mechanisms of acquired resistance include the activation of alternative pathways or downstream targets and histological transformation (i.e., epithelial–mesenchymal transition or conversion to small-cell lung cancer). Furthermore, the development of primary resistance through overexpression of the hepatocyte growth factor and suppression of Bcl-2-like protein 11 expression may lead to problems. In this report, we review these mechanisms and discuss therapeutic strategies to overcome resistance to EGFR-TKIs.

scholarly journals Acquired Resistance to Osimertinib Plus Savolitinib Is Mediated by MET-D1228 and MET-Y1230 Mutations in EGFR-Mutated MET-Amplified Lung Cancer

2020 ◽  
Vol 1 (4) ◽  
pp. 100071
Author(s):  
Andrew J. Piper-Vallillo ◽  
Brian T. Halbert ◽  
Deepa Rangachari ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa
Keyword(s):  
Lung Cancer ◽  
Acquired Resistance ◽  
Egfr Mutated

scholarly journals High expression of hypoxia inducible factor 1α related with acquired resistant to EGFR tyrosine kinase inhibitors in NSCLC

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qian Jin ◽  
Feihua Huang ◽  
Xianrong Xu ◽  
Haidong He ◽  
Yingqing Zhang
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Hypoxia Inducible Factor ◽  
High Expression ◽  
Normal Lung ◽  
Nsclc Tissue ◽  
T790m Mutation ◽  
Level Group ◽  
Egfr Tkis

AbstractThe acquired resistance of the first generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is a main factor leading to poor prognosis of non-small cell lung cancer (NSCLC), so we researched whether the high expression of hypoxia-inducible factor-1α (HIF-1α) in EGFR-TKIs sensitive NSCLC tissue tends to induce the acquired resistance. We detected the HIF-1α in normal lung tissue, EGFR-TKIs sensitive NSCLC tissue, the first generation EGFR-TKIs acquired resistant NSCLC tissue and acquired EGFR T790M mutation NSCLC tissue with the method of immunohistochemistry. Then, we compared the expression of HIF-1α in these tissues, and evaluate the effect of HIF-1α expression to the occurrence of acquired resistance. The expression of HIF-1α was much higher in the EGFR-TKIs sensitive NSCLC tissue than that in normal lung tissue. HIF-1α level became higher after the occurrence acquired resistance. There was negative correlation between HIF-1α level before receiving treatment and the time of acquired resistance occurring as well as the acquired EGFR T790M mutation occurring. As the treatment going on, EGFR-TKIs sensitivity rate of low HIF-1α level group was much higher than that of high level group. The high expression of HIF-1α related with the acquired resistance of the first generation EGFR-TKIs, and HIF-1α can be a biomarker to predict the early occurrence of acquired resistance.

scholarly journals Efficacy of the CDK4/6 Dual Inhibitor Abemaciclib in EGFR-Mutated NSCLC Cell Lines with Different Resistance Mechanisms to Osimertinib

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 6
Author(s):  
Silvia La Monica ◽  
Claudia Fumarola ◽  
Daniele Cretella ◽  
Mara Bonelli ◽  
Roberta Minari ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Nsclc Cell ◽  
Dual Inhibitor ◽  
Nsclc Patients ◽  
Egfr Mutated

Abemaciclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6 that inhibits the transition from the G1 to the S phase of the cell cycle by blocking downstream CDK4/6-mediated phosphorylation of Rb. The effects of abemaciclib alone or combined with the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib were examined in a panel of PC9 and HCC827 osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines carrying EGFR-dependent or -independent mechanisms of intrinsic or acquired resistance. Differently from sensitive cells, all the resistant cell lines analyzed maintained p-Rb, which may be considered as a biomarker of osimertinib resistance and a potential target for therapeutic intervention. In these models, abemaciclib inhibited cell growth, spheroid formation, colony formation, and induced senescence, and its efficacy was not enhanced in the presence of osimertinib. Interestingly, in osimertinib sensitive PC9, PC9T790M, and H1975 cells the combination of abemaciclib with osimertinib significantly inhibited the onset of resistance in long-term experiments. Our findings provide a preclinical support for using abemaciclib to treat resistance in EGFR mutated NSCLC patients progressed to osimertinib either as single treatment or combined with osimertinib, and suggest the combination of osimertinib with abemaciclib as a potential approach to prevent or delay osimertinib resistance in first-line treatment.

scholarly journals Real-world osimertinib for EGFR mutation-positive non-small-cell lung cancer with acquired T790M mutation

2020 ◽  
Vol 16 (21) ◽  
pp. 1537-1547
Author(s):  
Fumio Imamura ◽  
Madoka Kimura ◽  
Yukihiro Yano ◽  
Masahide Mori ◽  
Hidekazu Suzuki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Small Cell ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Clinical Trial Registration

Aim: Osimertinib is a key drug for EGFR mutation-positive non-small-cell lung cancer (NSCLC). As the hazards ratio of overall survival in comparison with first-generation EGFR-tyrosine kinase inhibitors was almost similar between FLAURA and ARCHER 1050, salvage use of osimertinib is still a treatment option. Patients & methods: We retrospectively analyzed the clinical courses of EGFR mutation-positive NSCLC patients who were potential candidates for salvage osimertinib. Results: Among 524 patients enrolled from five hospitals, 302 patients underwent biopsy, with 52.6% detection rate of T790M. Osimertinib was administered in 93.6% of the T790M-positive patients. The overall response rate and median progression-free survival time of osimertinib were calculated with 147 patients, to be 55.6% and 17.2 months, respectively. Conclusion: Osimertinib is active for T790M-driven acquired resistance in EGFR-mutant NSCLC, but the detection of T790M was unsatisfactory. Clinical Trial Registration: UMIN000028989 (UMIN Clinical Trials Registry)

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