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. 2021 Nov 17;7(47):eabk1023. doi: 10.1126/sciadv.abk1023

Fig. 1. G6PD is synthetic lethal with NRF2 activation and KEAP1 mutations.

Fig. 1.

(A) Schematic of pooled sgRNA library screen. KP (Keap1 WT) and KP + KI (Keap1 WT + Nrf2 activator) cells infected with sgRNA library virus were passaged for 14 population doublings before collection. (B) Enrichment of genes according to difference between KP + KI versus KP. Negative score signifies increased sensitivity in KP + KI cells. A full table is shown in table S1. (C) Proliferation of KP (Keap1 WT), KP treated with Nrf2 activator, or KPK [Keap1 knockout (KO)] cells with G6pd KO (n = 3). (D) Proliferation of KPK (Keap1 KO) overexpressing vector, Keap1 WT, or Keap1 LOF cDNA (G333C and R470C) cells with G6pd KO (n = 3). (E) Proliferation of KEAP1 WT or KEAP1 mutant human cell lines with sgG6PD-1 KO (n = 3). (F) Proliferation of NCI-H1299 (KEAP1 WT) and H1299 treated with NRF2 activator cells with G6PD KO (n = 3). (G) Proliferation of A549 (KEAP1 mutant) overexpressing KEAP1 WT or vector with G6PD KO (n = 3). (H) Relative viability of KP (Keap1 WT) and KP + KI (Keap1 WT + Nrf2 activator) treated with G6PDi-1 (G6PD inhibitor) for 3 days (n = 4). (I) Relative viability of KPK (Keap1 KO) overexpressing Keap1 WT or Vector treated with G6PDi-1 (G6PD inhibitor) for 3 days (n = 4). (J) Proliferation of HY19636 (Keap1 WT PDAC), DLD1 (KEAP1 WT colon cancer), and Calu-1 (KEAP1 WT lung squamous) treated with NRF2 activator cells or vehicle with G6PD KO (n = 3). **P < 0.01, ***P < 0.001, and ****P < 0.0001.