Hsu Chia-Chi, Yang Albert Ying-Po, Chen Jui-Yi, Tsai Hsin-Hui, Lin Shu-Heng, Tai Pei-Chen, Huang Ming-Hung, Hsu Wei-Hsun, Lin Anya Maan-Yuh, Yang James Chih-Hsin
Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Cancer Biology Research Group, Center of Precision Medicine, National Taiwan University, Taipei 100, Taiwan.
Cancers (Basel). 2021 Jan 13;13(2):272. doi: 10.3390/cancers13020272.
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.
表皮生长因子受体（EGFR）突变是非小细胞肺癌（NSCLC）中最常见的驱动基因，尤其是在亚洲人群中。尽管EGFR酪氨酸激酶抑制剂（TKIs）在治疗EGFR突变的NSCLC患者中具有重要作用，但不可避免地会出现获得性耐药。因此，迫切需要制定克服这种耐药性的策略。此外，具有特定突变的癌细胞似乎更容易受到与特定氨基酸可用性相关的缺乏的影响。然而，在EGFR突变的NSCLC病例中，哪种氨基酸受到影响仍然未知。在本研究中，我们建立了一个基于氨基酸剥夺的筛选平台，发现EGFR突变的NSCLC细胞对短期赖氨酸剥夺敏感。此外，我们发现赖氨酸分解代谢酶α-氨基己二酸转氨酶（AADAT）的基因表达在赖氨酸剥夺下增加，表明AADAT可受EGFR-AKT信号通路调节。最后，我们发现降低赖氨酸不仅可以增强单药奥希替尼的细胞生长抑制作用，还可以克服EGFR-TKIs在EGFR突变的NSCLC细胞中的耐药性。总之，我们的研究结果表明，引入赖氨酸应激可能是EGFR突变的NSCLC治疗的一个进展，并提供了一种克服EGFR-TKI耐药性的策略。
