Lysine Deprivation Induces AKT-AADAT Signaling and Overcomes EGFR-TKIs Resistance in EGFR-Mutant Non-Small Cell Lung Cancer Cells

SIMPLE SUMMARY: In the Asian population, 50–60% of non-small cell lung cancer (NSCLC) patients carry the epidermal growth factor receptor (EGFR) mutation. Although treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) is effective, resistance inevitably occurs. Moreover, previous studies showed that cancers harboring a specific mutation are sensitive to deficiency related to a particular amino acid. The identity of this amino acid is, however, unclear in the case of EGFR-mutant NSCLC. Our studies aim to identify the critical amino acid affected in EGFR-mutant NSCLC and develop a strategy against EGFR-TKI resistance. We determined that lysine is essential for the survival of EGFR-mutant NSCLC and EGFR-TKI-resistant sublines. In addition, we found that the presence of lysine reduction can lower the dosage of EGFR-TKI required for treatment in the case of EGFR-mutant NSCLC. Lastly, our findings provide a guiding principle showing that amino acid stress can enhance not only the therapeutic potential but also the quality of life for EGFR-mutant NSCLC patients. 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.