Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation
Activating mutations in EGFR and PI3K promote ATF4 induction for NSCLC cell survival during amino acid deprivation
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DOI：
10.1016/j.heliyon.2023.e14799
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发表时间：
2023-03-28
期刊：
影响因子：
4
通讯作者：
Tomida, Akihiro
中科院分区：
文献类型：
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作者：
Takahashi, Mizuki;Okamoto, Yuka;Tomida, Akihiro
一些癌蛋白沿着应激激酶一般控制非去阻遏蛋白2（GCN 2）可确保诱导激活转录因子4（ATF 4）以抵消氨基酸剥夺;然而，关于致癌EGFR-PI 3 K通路的作用知之甚少。在这项研究中，我们证明了突变的EGFR和PIK 3CA都有助于NSCLC细胞中GCN 2活化后的ATF 4诱导。EGFR或PI 3 K突变蛋白的抑制，直接或通过基因敲减，抑制了ATF 4诱导，而不影响GCN 2活化。下游分析显示，致癌EGFR-PI 3 K途径可能利用mTOR介导的翻译控制机制诱导ATF 4。此外，在携带EGFR和PIK 3CA共突变的NSCLC细胞中，这些癌蛋白的联合抑制显著抑制了ATF 4诱导和随后的基因表达程序以及氨基酸剥夺期间的细胞活力。我们的研究结果确立了致癌EGFR-PI 3 K通路在适应性应激反应中的作用，并提供了一种改善EGFR靶向NSCLC治疗的策略。
Some oncoproteins along with stress kinase general control non-derepressible 2 (GCN2) can ensure the induction of activating transcription factor 4 (ATF4) to counteract amino acid deprivation; however, little is known regarding the role of the oncogenic EGFR-PI3K pathway. In this study, we demonstrate that both mutated EGFR and PIK3CA contribute to ATF4 induction following GCN2 activation in NSCLC cells. The inhibition of EGFR or PI3K mutant proteins, pharmacologically or through genetic knockdown, inhibited ATF4 induction without affecting GCN2 activation. A downstream analysis revealed that the oncogenic EGFR-PI3K pathway may utilize mTOR-mediated translation control mechanisms for ATF4 induction. Furthermore, in NSCLC cells harboring co-mutations in EGFR and PIK3CA, the combined inhibition of these oncoproteins markedly suppressed ATF4 induction and the subsequent gene expression program as well as cell viability during amino acid deprivation. Our findings establish a role for the oncogenic EGFR-PI3K pathway in the adaptive stress response and provide a strategy to improve EGFR-targeted NSCLC therapy.