scholarly journals Correction to: “Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer”

2019 ◽  
Vol 30 (5) ◽  
pp. 858 ◽  
Author(s):  
C. Ricordel ◽  
L. Friboulet ◽  
F. Facchinetti ◽  
J.-C. Soria
Keyword(s):  
Lung Cancer ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Third Generation ◽  
Egfr T790m ◽  
Egfr Tkis

scholarly journals Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer

2018 ◽  
Vol 29 ◽  
pp. i28-i37 ◽  
Author(s):  
C. Ricordel ◽  
L. Friboulet ◽  
F. Facchinetti ◽  
J -C Soria
Keyword(s):  
Lung Cancer ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Third Generation ◽  
Egfr T790m ◽  
Egfr Tkis

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.

Treatment in EGFR-mutated Non-small Cell Lung Cancer: How to Block the Receptor and overcome Resistance Mechanisms

2017 ◽  
Vol 103 (4) ◽  
pp. 325-337 ◽  
Author(s):  
Claudia Proto ◽  
Giuseppe Lo Russo ◽  
Giulia Corrao ◽  
Monica Ganzinelli ◽  
Francesco Facchinetti ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Third Generation ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Exon 20 ◽  
Egfr Mutated ◽  
Egfr Tkis

In non-small cell lung cancer (NSCLC), the identification of epidermal growth factor receptor (EGFR) mutations and the parallel development of EGFR tyrosine kinase inhibitors (TKIs) have radically changed the therapeutic management strategies. Currently, erlotinib, gefitinib, and afatinib are all approved as standard first-line treatment in EGFR-mutated NSCLC. However, despite the proven efficacy, some EGFR-mutated NSCLCs do not respond to EGFR TKIs, while some patients, after a favorable and prolonged response to EGFR TKIs, inevitably progress within about 10-14 months. Epidermal growth factor receptor-dependent mechanisms, activation of alternative pathways, or phenotypic transformation can cause the resistance to EGFR TKIs. The exon 20 p.Thr790Met point mutation (T790M) is responsible for about 60% of cases of resistance when progression occurs. A third-generation TKI, osimertinib, improved outcome in patients harboring T790M after first- and second-generation TKI treatment. However, resistance develops even after treatment with third-generation drugs. To date, the Cys797Ser (C797S) mutation in exon 20 of EGFR is the most well-known resistance mutation after osimertinib. Fourth-generation TKIs are already under development. Nevertheless, additional information is needed to better understand and effectively overcome resistance. The aim of this review is to report recent advances and future perspectives in the treatment of EGFR-mutated NSCLC, highlighting the resistance mechanisms that underlie disease progression.

ERK Inhibitor ASN007 Effectively Overcomes Acquired Resistance to EGFR Inhibitor in Non-small Cell Lung Cancer

2021 ◽  
Author(s):  
Bo Mi Ku ◽  
Jae Yeong Heo ◽  
Jinchul Kim ◽  
Jong-Mu Sun ◽  
Se-Hoon Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Erk Signaling ◽  
Small Cell Lung ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Abstract The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Thus, development of effective strategies to overcome resistance to EGFR-TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR-TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR-TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR-TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR-TKIs synergistically decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR-TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR-TKIs by overcoming acquired resistance.

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