Optimizing CDK4/6 blockade in epithelioid sarcoma
| Epithelioid sarcoma (EPS) is a cancer caused by the loss of the SMARCB1 gene. EPS primarily occurs in adolescents and young adults and often becomes highly aggressive. Although the recent approval of the molecularly-targeted drug Tazemetostat offers a new treatment option for EPS, the response rate is only 15%, so most EPS patients do not benefit. To search for more effective EPS therapies, we conducted a comprehensive genetic study to identify potential therapeutic targets. We applied CRISPR/Cas9-mediated genetic screens to human EPS cell lines to characterize how deletion of thousands of genes affects EPS cancer cell survival. This revealed several potential vulnerabilities in EPS cancer cells and provided a comprehensive view of potential drug targets. Through target prioritization based on drug availability with success in other cancers, and our follow-up validation studies, we identified that cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in EPS cell growth. Importantly, CDK4/6 inhibitors are already used for patients with hormone receptor-positive breast cancer, where combining them with hormone therapy has dramatically improved patient outcomes. This inspired us to hypothesize that durable or potentially curative tumor remission is achievable in EPS when maximizing the anti-cancer activity of CDK4/6 inhibitor by combining it with other anti-cancer drugs. This study aims to identify the best combination drug approach with CDK4/6 inhibition through two complementary approaches. First, we will perform CRISPR screening in both human EPS cells and EPS mouse models treated with a CDK4/6 inhibitor. We will determine which gene, when inactivated, enhances the effect of the CDK4/6 inhibitor to reduce EPS cancer cell survival. Cell-based screens serve as an initial step to discover target genes that could be targeted by drugs, while screens in our novel mouse models can validate these results in conditions closer to those of patients. Second, we will study how EPS cancer cells develop resistance to CDK4/6 inhibitors by analyzing tumors that survive long-term drug treatment in mice. This analysis will reveal mechanisms that allow cancer cells to escape therapy and help identify targets to overcome resistance. The results from these approaches are complementary: large-scale screening provides new candidate drug targets and resistance analysis uncovers pathways EPS cancers use to survive with treatment with CDK4/6 inhibitors. Drug combinations suggested through this study will then be tested in cells and animal models using compounds that are already available either clinically for other cancers or under investigation in clinical trials. With these strategies, we aim to develop effective combination therapies for EPS that can achieve long-lasting control. This research may also provide insights for other cancers with SMARCB1 loss or those driven by the similar mechanisms. |