scholarly journals The Role of c-Met as a Biomarker and Player in Innate and Acquired Resistance in Non-Small-Cell Lung Cancer: Two New Mutations Warrant Further Studies

Molecules ◽  
2019 ◽  
Vol 24 (24) ◽  
pp. 4443
Author(s):  
Nele Van Der Steen ◽  
Karen Zwaenepoel ◽  
Giulia Mazzaschi ◽  
Rosa A. Luirink ◽  
Daan P. Geerke ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Egfr Mutations ◽  
Primary Therapy ◽  
Small Cell Lung ◽  
Primary Tumors ◽  
Egfr Expression

The c-Met receptor is a therapeutically actionable target in non-small-cell lung cancer (NSCLC), with one approved drug and several agents in development. Most suitable biomarkers for patient selection include c-Met amplification and exon-14 skipping. Our retrospective study focused on the frequency of different c-Met aberrations (overexpression, amplification and mutations) in 153 primary, therapy-naïve resection samples and their paired metastases, from Biobank@UZA. Furthermore, we determined the correlation of c-Met expression with clinicopathological factors, Epidermal Growth Factor Receptor (EGFR)-status and TP53 mutations. Our results showed that c-Met expression levels in primary tumors were comparable to their respective metastases. Five different mutations were detected by deep sequencing: three (E168D, S203T, N375S) previously described and two never reported (I333T, G783E). I333T, a new mutation in the Sema(phorin) domain of c-Met, might influence the binding of antibodies targeting the HGF-binding domain, potentially causing innate resistance. E168D and S203T mutations showed a trend towards a correlation with high c-Met expression (p = 0.058). We found a significant correlation between c-MET expression, EGFR expression (p = 0.010) and EGFR mutations (p = 0.013), as well as a trend (p = 0.057) with regards to TP53 mutant activity. In conclusion this study demonstrated a strong correlation between EGFR mutations, TP53 and c-Met expression in therapy-naïve primary resection samples. Moreover, we found two new c-Met mutations that warrant further studies.

Secondary T790M mutation and novel G796A mutation in exon20 of EGFR gene in patients with non-small cell lung cancer who show resistance to gefitinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7703-7703
Author(s):  
H. Uramoto ◽  
K. Sugio ◽  
T. Oyama ◽  
T. Iwata ◽  
T. Onizuka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Missense Mutation ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Egfr Gene

7703 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI. No significant financial relationships to disclose.

scholarly journals AI-Based Drug Discovery of TKIs Targeting L858R/T790M/C797S-Mutant EGFR in Non-small Cell Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Geunho Choi ◽  
Daegeun Kim ◽  
Junehwan Oh
Keyword(s):  
Lung Cancer ◽  
Drug Discovery ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Anticancer Agents ◽  
Short Term Memory ◽  
Acquired Resistance ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung

Lung cancer has a high mortality rate, and non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Patients have been observed to acquire resistance against various anticancer agents used for NSCLC due to L858R (or Exon del19)/T790M/C797S-EGFR mutations. Therefore, next-generation drugs are being developed to overcome this problem of acquired resistance. The goal of this study was to use artificial intelligence (AI) to discover drug candidates that can overcome acquired resistance and reduce the limitations of the current drug discovery process, such as high costs and long durations of drug design and production. To generate ligands using AI, we collected data related to tyrosine kinase inhibitors (TKIs) from accessible libraries and used LSTM (Long short term memory) based transfer learning (TL) model. Through the simplified molecular-input line-entry system (SMILES) datasets of the generated ligands, we obtained drug-like ligands via parameter-filtering, cyclic skeleton (CSK) analysis, and virtual screening utilizing deep-learning method. Based on the results of this study, we are developing prospective EGFR TKIs for NSCLC that have overcome the limitations of existing third-generation drugs.

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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