Lysine deprivation induces AKT-AADAT signaling and overcomes EGFR-TKIs resistance in EGFR-mutant non-small cell lung cancer cells

Chia Chi Hsu, Albert Ying Po Yang, Jui Yi Chen, Hsin Hui Tsai, Shu Heng Lin, Pei Chen Tai, Ming Hung Huang, Wei Hsun Hsu, Anya Maan Yuh Lin*, James Chih Hsin Yang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) mutations are the most common driver genes in non-small cell lung cancer (NSCLC), especially in the Asian population. Although EGFR-tyrosine kinase inhibitors (TKIs) are influential in the treatment of EGFR-mutant NSCLC patients, acquired resistance inevitably occurs. Therefore, there is an urgent need to develop strategies to overcome this resistance. In addition, cancer cells with particular mutations appear more vulnerable to deficiency related to the availability of specific amino acids. However, it is still unknown which amino acid is affected in the case of EGFR-mutant NSCLC. In the present study, we established a screening platform based on amino acid deprivation and found that EGFR-mutant NSCLC cells are sensitive to short-term lysine deprivation. Moreover, we found that expression of the gene for the lysine catabolism enzyme α-aminoadipate aminotransferase (AADAT) increased under lysine deprivation, revealing that AADAT can be regulated by EGFR-AKT signaling. Finally, we found that lysine reduction can not only enhance the cytostatic effect of single-agent osimertinib but also overcome the resistance of EGFR-TKIs in EGFR-mutant NSCLC cells. In summary, our findings suggest that the introduction of lysine stress might act as an advancement in EGFR-mutant NSCLC therapy and offer a strategy to overcome EGFR-TKI resistance.

Original languageEnglish
Article number272
Pages (from-to)1-17
Number of pages17
JournalCancers
Volume13
Issue number2
DOIs
StatePublished - 2 Jan 2021

Keywords

  • AADAT
  • EGFR-mutant NSCLC
  • EGFR-TKI resistance
  • Lysine deprivation
  • Osimertinib

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