Abstract 4139: Targeting USP10 to enhance chemotherapy and immunotherapy in NSCLC

Abstract Non-small cell lung cancer (NSCLC) remains a leading cause of death from cancer. While platinum-based chemotherapy is initially effective for early-stage NSCLC, drug resistance often limits its long-term success. Combining platinum-based chemotherapy with immunotherapy has emerged as a first-line treatment for metastatic NSCLC. However, many patients still experience limited benefits due to various resistance mechanisms. One critical mechanism underlying drug resistance is the increased capacity of DNA damage response (DDR). The deubiquitinase USP10 plays a crucial role in regulating the DDR by stabilizing oncogene proteins such as HDAC6. Inhibition of USP10 disrupts the USP10-HDAC6 axis, leading to enhanced DNA damage and cell death. Further, HDAC6 inhibition enhances immunogenic cell death-inducing radiotherapy-induced immune responses. Furthermore, HDAC6 inhibition leads to decreased expression of CD47 that acts as a "don't eat me" signal to prevent immune cells from phagocytosing tumor cells. Based on these findings, we hypothesize that targeting USP10 leads to HDAC6 degradation and DNA damage, resulting in sensitization of NSCLC cells to chemotherapy. Additionally, we propose that USP10 inhibition can sensitize NSCLC cells to immune checkpoint inhibitors and immunotherapy targeting CD47. Our extensive computational and structure-activity-relationship (SAR) studies led to the discovery of potent USP10 inhibitors. Our preliminary data show that the lead compound, GL-320, selectively inhibits USP10 activity, as confirmed by in vitro deubiquitinase (DUB) and cellular thermal shift assays. GL-320 dose-dependently inhibited the in vitro cell proliferation of H1299, a p53 null lung cancer cell, whereas it was significantly less effective against A549 cells with w/t p53. We also show that by inhibiting USP10, we can disrupt the DDR pathway, leading to increased DDR and cell death, as confirmed by western blotting and flow cytometry analyses. Our preliminary data show that USP 10 is a validated drug target to enhance the efficacy of existing chemotherapy and immunotherapy in NSCLC. Citation Format: Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh, Babita Kushwaha, Prahlad Parajuli, Yubin Ge, Navnath S. Gavande. Targeting USP10 to enhance chemotherapy and immunotherapy in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4139.