Elucidating the Target and Selectivity of a Non-Small Cell Lung Cancer Toxin

Selective toxicity among cancer cells of the same lineage is a hallmark of targeted therapies, and so identifying compounds that impair proliferation selectively is an important strategy in drug development. Here, we report the discovery of the quinazoline dione compound (QDC), a molecule that exhibits selective toxicity across 100 non-small cell lung cancer (NSCLC) lines. Using photoreactive probes, we found that the QDC targets mitochondrial Complex I. We investigated the selective toxicity of Complex I inhibition across NSCLC and found that a high baseline content of aspartate formed via reductive glutamine metabolism promotes resistance to mitochondrial inhibition. Altered metabolism is an important feature of cancer and there is significant interest in understanding how differences in tumor metabolism can be exploited for therapy. NSCLC cells subject to mitochondrial inhibition use reductive carboxylation to meet aspartate demand, which suggests that targeting reductive aspartate synthesis would enhance clinical response to Complex I inhibitors.