Cells Lacking the <i>RB1</i> Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival.

Abstract

Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating <i>RB1</i> and <i>TP53</i> mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the <i>RB1</i> gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an <i>RB1</i> ^-/- SCLC cell line that conditionally expresses <i>RB1</i> to identify dependencies that are caused by RB1 loss and discovered that <i>RB1</i> ^-/- SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other <i>RB1</i> ^-/- cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that <i>RB1</i> ^-/- SCLC are hyperdependent on <i>AURKB</i>, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against <i>RB1</i> ^-/- SCLC tumors in mice at nontoxic doses.<i>See related commentary by Dick and Li, p. 169</i>.<i>This article is highlighted in the In This Issue feature, p. 151</i>.