Targeting the USP2-POU2F3 signaling pathway for small cell lung cancer (SCLC-P) treatment

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Abstract

Project Summary/Abstract: Small cell lung cancer (SCLC) is a highly aggressive form of neuroendocrine carcinoma, accounting for approximately 15% of all lung cancers. SCLC is a heterogeneous disease, broadly categorized into four molecular subtypes: neuroendocrine subtypes driven by ASCL1 (60%) and NEUROD1 (20%), and non-neuroendocrine subtypes marked by the POU family transcription factor POU2F3 (10-12%) or an inflammatory subtype (10%). More importantly, the high expression of ASCL1, NEUROD1, and POU2F3 is not only a stratifying biomarker, but also presents promising therapeutic opportunities, as these transcription factors represent selective dependencies in SCLC, depletion of which leads to cell death for the particular subtype. Specifically, the POU2F3-positive small cell lung cancer subtype (SCLC-P) is heavily reliant on POU2F3 for survival and growth. However, the upstream regulatory pathways controlling POU2F3 expression, particularly through post-translational modifications, remain largely unexplored. Thus, elucidating the molecular mechanisms that regulate POU2F3 protein homeostasis and identifying strategies to reduce its protein abundance may open new therapeutic avenues for SCLC-P. In this proposal, I have accumulated preliminary studies to identify APCCDC20 as a potential E3 ubiquitin ligase that promotes POU2F3 proteasomal degradation through mediating plolyubiquitination of the POU2F3 oncoprotein. Conversely, USP2 has been identified as a potential deubiquitinase that stabilizes POU2F3 by removing its ubiquitin chains. Importantly, USP2 inhibitors have demonstrated the ability to induce significant degradation of POU2F3 and suppress cell growth in SCLC-P settings. In the first aim of this study, I will explore the molecular mechanism and the physiological role of APCCDC20 in regulating POU2F3 ubiquitination and protein stability in SCLC-P (Aim #1). In the second aim, I will assess the critical role of USP2 in stabilizing POU2F3 oncoprotein and evaluate its potential as a therapeutic target in SCLC-P (Aim #2). Collectively, these proposed studies will allow me to reveal a dynamic regulatory mechanism for POU2F3 protein homeostasis involving the E3 ligase CDC20 and the deubiquitinase USP2, with clinical implications for retarding SCLC-P tumorigenesis in vivo. This study will also provide a strong rationale for targeting USP2 with specific inhibitors as a potential therapeutic strategy for treating SCLC-P patients in future clinic practice.