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Keap1 mutations that activate Nrf2 result in elevated GSH production thereby leaving Keap1 mutant cells highly dependent on glutaminolysis and susceptible to glutaminase inhibition in vitro. However, the extracellular environment can greatly affect cellular metabolism, and culturing cells in vitro versus in vivo can significantly alter their metabolic requirements ( Davidson et al., 2016 ). To assess the importance of xCT/Slc7a11 in driving sensitivity to glutaminase inhibition in KPK cells in vivo, we implanted KP and KPK cells that expressed inducible shRNA constructs against Slc7a11 or CTRL subcutaneously in mice. After tumors were established, mice were randomized to groups to receive oral CB-839 or vehicle twice daily and to receive a doxycycline or control diet to induce shRNA expression. CB-839 treatment suppressed tumor growth only in KPK cells, but had no effect on KP tumors ( Figure 2G and H and Figure 2—figure supplement 2D and E ). Knockdown of Slc7a11 completely abrogated the effect of CB-839 on KPK tumors ( Figure 2H and Figure 2—figure supplement 2E ). These data strongly support the notion that Keap1 mutations result in a metabolic liability to glutaminase inhibition in vivo driven by increased expression of xCT/Slc7a11 in KPK cells.