Cancer cells reprogram their metabolism, altering both uptake and utilization of extracellular nutrients. We individually depleted amino acid nutrients from isogenic cells expressing commonly activated oncogenes to identify correspondences between nutrient supply and viability. In HME (human mammary epithelial) cells, deprivation of cystine led to increased cell death in cells expressing an activated epidermal growth factor receptor (EGFR) mutant. Cell death occurred via synchronous ferroptosis, with generation of reactive oxygen species (ROS). Hydrogen peroxide promoted cell death, as both catalase and inhibition of NADPH oxidase 4 (NOX4) blocked ferroptosis. Blockade of EGFR or mitogen-activated protein kinase (MAPK) signaling similarly protected cells from ferroptosis, whereas treatment of xenografts derived from EGFR mutant non-small-cell lung cancer (NSCLC) with a cystine-depleting enzyme inhibited tumor growth in mice. Collectively, our results identify a potentially exploitable sensitization of some EGFR/MAPK-driven tumors to ferroptosis following cystine depletion.

Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor‐2 (FGF‐2) increases the expression of antiapoptotic proteins, XIAP and Bcl‐XL, and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B‐Raf, PKCε and S6K2. S6K1, Raf‐1 and other PKC isoforms do not form similar complexes. RNAi‐mediated downregulation of B‐Raf, PKCε or S6K2 abolishes FGF‐2‐mediated survival. In contrast, overexpression of PKCε increases XIAP and Bcl‐XL levels and chemoresistance in SCLC cells. In a tetracycline‐inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl‐XL and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling.

Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of 6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3′-deoxy-3′-[¹⁸F]fluorothymidine–positron emission tomography ([¹⁸F]FLT-PET) showed decreased intratumoral proliferation in live animals treated with the compound at 7 to 14 days. Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that [¹⁸F]FLT-PET imaging could provide early in vivo evidence of response. [Cancer Res 2009;69(22):8645–51]

The involvement of fibroblast growth factor-2 (FGF-2) in the biology of small cell lung cancer (SCLC) has not previously been investigated. Here we report that FGF-2 prevented etoposide-induced apoptosis in H-510 SCLC cells. Phosphatidylinositol 3-kinase/protein kinase B signaling did not mediate this effect because FGF-2 failed to activate phosphatidylinositol 3-kinase or protein kinase B. In contrast, the mitogen-activated extracellularly regulated kinase kinase (MEK) was crucial for this response because its inhibition abolished the prosurvival properties of FGF-2. Moreover, in H-69 SCLC cells, the failure of FGF-2 to prevent etoposide-induced apoptosis correlated with uncoupling from MEK activation. However, the introduction of an activated MEK rendered these cells resistant to etoposide killing. Cell rescue relied on de novo protein synthesis, and the anti-apoptotic proteins Bcl-X_L and Bcl-2 were up-regulated in a MEK-dependent fashion within 4 h of FGF-2 treatment. Contrary to previous reports, we found that this up-regulation occurred at the translational rather than the transcriptional level. Indeed, actinomycin D failed to prevent up-regulation of Bcl-X_L and Bcl-2, and FGF-2 did not increase the mRNA levels or the stability of these proteins. The induction of the pro-apoptotic protein Bad by etoposide was also blocked by FGF-2 in a MEK-dependent fashion. Thus, MEK/extracellularly regulated kinase signaling is critical in the coordinate modulation of both pro- and anti-apoptotic Bcl-2 family members by FGF-2.