Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in <i>RB1</i> -Deficient Human and Mouse Small-Cell Lung Cancer

Abstract

The <i>RB1</i> tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with <i>TP53</i>, is required and sufficient for tumorigenesis. While <i>RB1</i>-mutant cells fail to arrest at G₁-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat <i>RB1</i>-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in <i>Rb1/Trp53</i>-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have <i>in vivo</i> antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in <i>RB1</i>-deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of <i>RB1</i>, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.