The EGFR T790M mutation is acquired through AICDA-mediated deamination of 5-methylcytosine following TKI treatment in lung cancer.

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 TKI. Whether T790M mutation is acquired or is selected from a pre-existing clone has been a matter of significant debate. In this study, we show that treatment with EGFR TKI leads to activation of the NFᴋB 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 NFᴋB 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.

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