SummaryCancer 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.
The existence of multiple centrosomes in some cancer
cells can
lead to cell death through the formation of multipolar mitotic spindles
and consequent aberrant cell division. Many cancer cells rely on HSET
(KIFC1) to cluster the extra centrosomes into two groups to mimic
the bipolar spindle formation of non-centrosome-amplified cells and
ensure their survival. Here, we report the discovery of a novel 2-(3-benzamidopropanamido)thiazole-5-carboxylate
with micromolar in vitro inhibition of HSET (KIFC1) through high-throughput
screening and its progression to ATP-competitive compounds with nanomolar
biochemical potency and high selectivity against the opposing mitotic
kinesin Eg5. Induction of the multipolar phenotype was shown in centrosome-amplified
human cancer cells treated with these inhibitors. In addition, a suitable
linker position was identified to allow the synthesis of both fluorescent-
and
trans
-cyclooctene (TCO)-tagged probes, which
demonstrated direct compound binding to the HSET protein and confirmed
target engagement in cells, through a click-chemistry approach.
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