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

Epidermal growth factor receptor () 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 -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 -mutant NSCLC. In the present study, we established a screening platform based on amino acid deprivation and found that -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 () increased under lysine deprivation, revealing that 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 -mutant NSCLC cells. In summary, our findings suggest that the introduction of lysine stress might act as an advancement in -mutant NSCLC therapy and offer a strategy to overcome EGFR-TKI resistance.