Fig. 7: Working model depicting the mechanism that KEAP1 deficiency sensitizes NSCLC cells to AURKA inhibition. | Cell Death & Disease

Fig. 7: Working model depicting the mechanism that KEAP1 deficiency sensitizes NSCLC cells to AURKA inhibition.

From: AURKA emerges as a vulnerable target for KEAP1-deficient non-small cell lung cancer by activation of asparagine synthesis

Fig. 7: Working model depicting the mechanism that KEAP1 deficiency sensitizes NSCLC cells to AURKA inhibition.

In KEAP1 mutant (MUT) tumor cells, the NRF2 pathway is activated, leading to the increase in the consumption of glutamate for GSH synthesis and the export of glutamate outside the cell through SLC7A11 in exchange for cystine, compared with KEAP1 wildtype (WT) cells. Reduced intercellular glutamate level results in activation of GCN2 and eIF2α phosphorylation and ATF4-mediated ASNS expression in KEAP1 mutant tumor cells. AURKA interacts with GCN2 and eIF2α, and AURKA inhibition using its kinase inhibitors such as MLN8237 can remarkably suppress the activated GCN2-eIF2α-ATF4-ASNS axis in KEAP1 mutant tumor cells, resulting in a significant decrease in asparagine levels, increased apoptosis, and further inhibition of cell proliferation.

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