Abstract 537: Validating USP27X as a drug target in lung cancer

Abstract Over the past two decades, tremendous efforts have been dedicated to developing and improving receptor tyrosine kinase (RTK) targeted therapies to combat the development and progression of different cancers. Despite the significant progress made, these therapies are not durable: not all patients respond to treatment, and primary or acquired resistances are common. Interestingly, however, while RTK-targeted therapies have no effect on resistant lung cancer cell lines, si/shRNA-mediated RTK depletion or combined treatments that affect RTK protein levels profoundly impact the growth and survival of these cells, indicating that RTKs are still critical for their proliferation. Thus, strategies to target RTK protein levels hold promise as an option for treating RTK-driven cancers. In our recent studies, we discovered that ubiquitin-specific protease 27X (USP27X) functions are crucial for properly recycling and maintaining EGFR steady-state levels in lung cancer cells. Ablation of USP27X leads to a severe decrease of EGFR steady levels, inhibition of xenograft tumor growth, and sensitization of lung cancer cell lines to targeted therapy. To fully understand the in vivo functions of USP27X in EGFR regulation and lung carcinogenesis, we created a new mouse line carrying a conditional Usp27X allele and introduced this allele into the well-established and clinically relevant EGFRL858R mouse lung cancer model. Ongoing studies will determine whether USP27X can be a critical therapeutic in EGFR-driven lung cancer. Citation Format: Shamshad Alam, Amanda Zunic, Swati Venkat, Michael E Feigin, Boyko Atanassov. Validating USP27X as a drug target in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 537.