The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer

Kadi, Najwa El; Luo, Wei; Davis, April; Korkaya, Hasan; Cooke, Alexander; Vadnala, Varun; Brown, Noah A.; Betz, Bryan L.; Cascalho, Marília; Kalemkerian, Gregory P.; Hassan, Khaled A.

doi:10.1158/0008-5472.can-17-3370

Cited by 28 publications

(24 citation statements)

References 40 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to El Kadi and coworkers, the formation of EGFR T790M mutation is initiated by AICDA-mediated deamination of the 5-methylcytosine following therapy with either of the EGFR TKI. Nevertheless they observed differential gene expression of AICDA under different treatment conditions (type and dose of EGFR TKI) [25]. Therefore, a different frequency of T790M acquisition under reversible and irreversible EGFR TKI is conceivable.…”

Section: Discussionmentioning

confidence: 97%

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

et al. 2020

View full text Add to dashboard Cite

Background: Over the past years, EGFR tyrosine kinase inhibitors (TKI) revolutionized treatment response. 1stgeneration (reversible) EGFR TKI and later the 2nd-generation irreversible EGFR TKI Afatinib were aimed to improve treatment response. Nevertheless, diverse resistance mechanisms develop within the first year of therapy. Here, we evaluate the prevalence of acquired resistance mechanisms towards reversible and irreversible EGFR TKI. Methods: Rebiopsies of patients after progression to EGFR TKI therapy (> 6 months) were targeted to histological and molecular analysis. Multiplexed targeted sequencing (NGS) was conducted to identify acquired resistance mutations (e.g. EGFR p.T790M). Further, Fluorescence in situ hybridisation (FISH) was applied to investigate the status of bypass mechanisms like, MET or HER2 amplification. Results: One hundred twenty-three rebiopsy samples of patients that underwent first-line EGFR TKI therapy (PFS ≥6 months) were histologically and molecularly profiled upon clinical progression. The EGFR p.T790M mutation is the major mechanism of acquired resistance in patients treated with reversible as well as irreversible EGFR TKI. Nevertheless a statistically significant difference for the acquisition of T790M mutation has been identified: 45% of afatinib-vs 65% of reversible EGFR TKI treated patients developed a T790M mutation (p-value 0.02). Progression free survival (PFS) was comparable in patients treated with irreversible EGFR irrespective of the sensitising primary mutation or the acquisition of p.T790M. Conclusions: The EGFR p.T790M mutation is the most prominent mechanism of resistance to reversible and irreversible EGFR TKI therapy. Nevertheless there is a statistically significant difference of p.T790M acquisition between the two types of TKI, which might be of importance for clinical therapy decision.

show abstract

Section: Discussionmentioning

confidence: 97%

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The mechanism of acquisition T790M is still unclear. El Kadi et al reported that deamination of the 5-methylcytosine to thymidine at position c.2369 generates the T790M change that alters TKI-binding affinity and causes resistance ( 24 ). In addition, the BELIEF trial showed that T790M at disease progression can be derived from the selection of preexisting EGFR T790M-positive clones or emerge de novo in initially negative cells ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

An Observational Study of Acquired EGFR T790M-Dependent Resistance to EGFR-TKI Treatment in Lung Adenocarcinoma Patients in Taiwan

Chiang

Liu

et al. 2020

Front. Oncol.

View full text Add to dashboard Cite

show abstract

“…Early diagnosis and innovations in the treatment of lung cancer have contributed towards improving the survival rate of patients. Currently, patients with EGFR-mutant NSCLC are administered a standard treatment regimen of EGFR-TKIs as they demonstrate better response rates and PFS as compared to chemotherapy 24,25. Unfortunately, almost all EGFR-mutant NSCLC patients who received first-generation EGFR-TKI therapy developed secondary drug resistance with a mean PFS range of 9.2–13.1 months 25.…”

Section: Discussionmentioning

confidence: 99%

<p>FGFR1 Induces Acquired Resistance Against Gefitinib By Activating AKT/mTOR Pathway In NSCLC</p>

Zhang¹,

Han²,

Du³

et al. 2019

OTT

View full text Add to dashboard Cite

ObjectiveAs an epidermal growth factor, receptor-tyrosine kinase inhibitor (EGFR-TKI), gefitinib demonstrates a good therapeutic effect in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, an overwhelming majority of these patients inevitably develop resistance against gefitinib. Unfortunately, the mechanism underlying this phenomenon is still not fully understood. Here we aim to reveal the mechanism of gefitinib resistance in NSCLC induced by FGFR1.Materials and methodsWe used high-throughput sequencing to compare the mRNA expression profiles of PC9 and PC9-GR (gefitinib-resistant) cells. The clinical significance of fibroblast growth factor receptor 1 (FGFR1) in NSCLC was also investigated using immunohistochemistry and Kaplan-Meier survival analysis. Finally, the in vitro molecular mechanisms were analyzed using confocal laser microscopy, Western blotting, transwell assay, colony formation assay, CCK-8 assay, and apoptosis assay.ResultsWe observed that FGFR1 was highly expressed in NSCLC tissues and was closely associated with poor prognosis. Cytological experiments showed that FGFR1 promoted the proliferation and migration of PC9-GR cells and mediated their resistance to gefitinib. Furthermore, studies aimed at unraveling this mechanism revealed that FGFR1 activated the AKT/mTOR signaling pathway. These findings show that the FGFR1/AKT/mTOR signaling pathway plays a vital role in acquired resistance against gefitinib in NSCLC.ConclusionThis work provides new evidence that FGFR1 functions as a key regulator of gefitinib resistance, thereby demonstrating its potential as a novel biomarker and therapeutic target for NSCLC.

show abstract

The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer

Cited by 28 publications

References 40 publications

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors

An Observational Study of Acquired EGFR T790M-Dependent Resistance to EGFR-TKI Treatment in Lung Adenocarcinoma Patients in Taiwan

<p>FGFR1 Induces Acquired Resistance Against Gefitinib By Activating AKT/mTOR Pathway In NSCLC</p>

Contact Info

Product

Resources

About