Noncanonical Function of STING in ccRCC
Abstract
ccRCC (clear cell renal cell carcinoma) accounts for the majority of kidney cancer, where inactivation of a gene called VHL and hyperactivation of another gene called PI3K are frequently observed. However, therapies targeting these signaling pathways showed limited clinical benefits. Thus, new treatment regimens are urgently needed. Aiming to identify new drug targets and treatment options for ccRCC patients, we found that a gene named STING, with a known cellular function in clearing viral or bacterial infection, is a novel vulnerability and drug target in ccRCC. In addition, we found a chemical compound that was able to slow down ccRCC cell growth through regulating the novel STING function we found. This proposal addresses the FY20 KCRP research focus area as a basic scientific research project to gain a deeper knowledge of kidney cancer pathogenesis and identify mechanisms for responses and resistance to treatments. Specifically, we found that the innate immune sensor STING was highly expressed in 14% of ccRCC patients. This is surprising given that we expect to observe deficiency in STING function in ccRCC, since evading immune destruction is a hallmark of cancer. This unexpected finding led us to hypothesize that, distinct from other cancer types, ccRCC tumors rely on high levels of STING for survival, and targeted reduction of STING levels in these patients may provide a cure. In support of this notion, we observed that loss of STING in ccRCC cells led to reduced cell growth in vitro. Moreover, we found STING maintains RCC tumor growth through maintaining cellular oxidative stress levels and proper cell cycle progression, which is independent of its original roles in innate immunity. We were excited to find that a compound called erastin efficiently reduced ccRCC cell growth by disrupting STING function in this specific cellular process. We think that there is a group of ccRCC patients (~14%) bearing high levels of STING expression that may specifically benefit from this treatment regimen. The proposed study is a combination of identification and validation of STING as a new drug target for treating ccRCC, from mechanistic studies to preclinical tests. Characterization of proposed features in cell culture model, mouse model, and human patient samples may provide biomarkers for ccRCC diagnosis and prognosis. Proposed preclinical tests of the effects of erastin treatment alone, or in combination with approved ccRCC-targeted therapeutic agents, will boost its potential clinical usage to benefit ccRCC patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110419
Entities
People
- Pengda Liu
Organizations
- United States Army
- University of North Carolina at Chapel Hill