Deciphering the Critical Roles of USP22 in Carcinogenesis and Cross-Talk Between Cancer and Immune Cells for Non-Small Cell Lung Cancer Therapy
Abstract
Scientific Objective and Rationale: Oncogenic KRAS mutations are the most frequent mutations that drive the development of non-small cell lung cancer (NSCLC), and unfortunately, they are also the most difficult to effectively treat. Although targeted therapy is available for a type of KRAS mutant cancer, KRAS inhibition is short-lived due to the development of resistance and immune defects. The median overall survival for all patients with KRAS mutant advanced lung cancers is only 14 months. Therefore, novel therapies are still urgently needed for these patients. We hypothesize that targeting ubiquitin-specific peptidase 22 (USP22) will meet this need. First, USP22 is critical for cancer progression, and its expression in lung cancer positively correlates with drug resistance, metastasis, recurrence, and shorter survival of cancer patients. Consistent with this, we showed that USP22 deletion in KRAS mutant NSCLC cell lines drastically suppressed in vivo blood vessel formation, growth, and metastasis of cancer xenografts, while dramatically prolonging the survival of metastatic lung cancer-bearing mice. We also showed that USP22 deletion sensitized KRAS mutant NSCLC to cisplatin and irradiation. Second, USP22 promotes cancer immune escape. USP22 can enhance both regulatory T and cancer cells’ suppression on anticancer immunity. Area(s) of Emphasis: The proposal addresses three LCRP areas of emphasis; it will: 1. Identify innovative strategies for the treatment of lung cancer, 2. Identify innovative strategies for the prevention of recurrence of lung cancer, and 3. Increase our understanding of the molecular mechanisms of initiation and progression to lung cancer. Applicability of the Proposed Research: Veterans are disproportionately affected by lung cancer due to smoking and occupational carcinogen exposure. On average, Veterans have significantly lower rates of other druggable mutations and a higher rate of KRAS mutation compared to the general population. This application will focus on KRAS-mutant lung cancer and develop a novel target that may increase the effectiveness of immunotherapy and chemotherapy. The ultimate goal of this proposal is to develop USP22-targeted therapy by potent and selective inhibitors for the treatment of NSCLC. Currently, there is no selective inhibitor of USP22 available. We have developed a candidate USP22 inhibitor that we will use as a biochemical probe in preclinical studies. Because USP22 inhibition induces broad anti-cancer activities through suppressing cancer and boosting host antitumor immunity, USP22 inhibition will potentially overcome resistance to chemo-radiotherapy and immune checkpoint blockage. Although, a potential risk of USP22 inhibition may be development of autoimmune disease due to enhanced immunity, the side effect will be moderate and tolerable. USP22 inhibition will be particularly effective against KRAS-Mut NSCLC due to its immunosuppressive tumor microenvironment. It will also be applied to other NSCLC without mutant KRAS patients whose cancers have high USP22. Successful completion of the proposed aims within next 2 years will achieve a clinically relevant outcome, provide the first fundamental insights into the function of USP22 in carcinogens and immune escape, and lay the groundwork for developing potent, selective USP22 inhibitors that will be used alone or in combination with chemo-radiotherapy and immunotherapy for lung cancer treatment, especially for lung cancers with oncogenic KRAS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210306
Entities
People
- Dan Raz
Organizations
- Beckman Research Institute of City of Hope
- United States Army