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

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Almost all patients with EGFR-driven lung cancer who are treated with EGFR tyrosine kinase inhibitors (TKI) develop resistance to treatment. A single base (c.2369C>T) transition mutation, EGFR T790M, is the most frequent resistance event after first-generation exposure to EGFR TKIs. Whether T790M mutation is acquired or is selected from a preexisting clone has been a matter of significant debate. In this study, we show that treatment with EGFR TKIs leads to activation of the NFkB pathway, which in turn induces expression of activation-induced cytidine deaminase (AICDA). In turn, AICDA causes deamination of 5-methylcytosine to thymine at position c.2369 to generate the T790M mutation. Pharmacologic inhibition of the NFkB pathway or knockout of AICDA decreased the frequency or prevented the development of T790M mutation, respectively. In addition, patients treated with first-line EGFR TKI displayed increased expression of AICDA and detection of the T790M mutation upon progression. These results identify the mechanism of T790M acquisition and present an opportunity to target the process to delay or prevent it. Significance: These findings identify the mechanism behind acquisition of a common resistance mutation to TKI treatment in lung cancer.

Original languageEnglish (US)
Pages (from-to)6728-6735
Number of pages8
JournalCancer Research
Volume78
Issue number24
DOIs
StatePublished - Dec 15 2018

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5-Methylcytosine
Deamination
Protein-Tyrosine Kinases
Lung Neoplasms
Mutation
Therapeutics
Thymine
AICDA (activation-induced cytidine deaminase)
Clone Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer. / Kadi, Najwa El; Wang, Luo; Davis, April; Korkaya, Hasan; Cooke, Alexander; Vadnala, Varun; Brown, Noah A.; Betz, Bryan L.; Cascalho, Marilia; Kalemkerian, Gregory P.; Hassan, Khaled A.

In: Cancer Research, Vol. 78, No. 24, 15.12.2018, p. 6728-6735.

Research output: Contribution to journalArticle

Kadi, NE, Wang, L, Davis, A, Korkaya, H, Cooke, A, Vadnala, V, Brown, NA, Betz, BL, Cascalho, M, Kalemkerian, GP & Hassan, KA 2018, 'The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer', Cancer Research, vol. 78, no. 24, pp. 6728-6735. https://doi.org/10.1158/0008-5472.CAN-17-3370
Kadi, Najwa El ; Wang, Luo ; Davis, April ; Korkaya, Hasan ; Cooke, Alexander ; Vadnala, Varun ; Brown, Noah A. ; Betz, Bryan L. ; Cascalho, Marilia ; Kalemkerian, Gregory P. ; Hassan, Khaled A. / The EGFR T790M Mutation Is Acquired through AICDA-Mediated Deamination of 5-Methylcytosine following TKI Treatment in Lung Cancer. In: Cancer Research. 2018 ; Vol. 78, No. 24. pp. 6728-6735.
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