A Novel Peptide Suppresses Invasion and Metastasis in Rictor-Amplified Lung Cancer
Abstract
Lung cancer is the most commonly diagnosed cancer and the first leading cause of death in both men and women, including active-duty Service Members, Veterans, and their families in the United States. The high death rate is not only due to lack of effective early detection, but also to poor tumor response to currently available treatment, especially at the late stage of this disease. Lung cancers are classified into two types: small cell lung cancers (SCLC) and non-small cell lung cancers (NSCLC). Recent studies have recognized that Rapamycin-insensitive companion of mTOR (Rictor) gene is amplified in both SCLC and NSCLC. Rictor amplification in lung cancer cells increase tumor cell proliferation, migration, and invasion. Recent studies also showed that Rictor-amplified lung cancer cells are more sensitive to mammalian target of rapamycin complex 1/complex 2 (mTORC1/C2) dual inhibitors than other chemotherapy drugs. However, mTORC1 inhibition induces cancer cell survival, and mTOCR1-specific inhibitors show very limited response in lung cancer patients. On the other hand, mTORC2-specific inhibition has the advantage of not disturbing the mTORC1-induced cell survival, providing the fascinating potential for a novel therapeutic. Unfortunately, this idea has not been thoroughly examined yet. This proposal builds on exciting preliminary data that a novel RBD peptide specifically inhibits mTORC2 but not mTORC1 activity. The RBD peptide, thus, provides a unique tool to study the effects of specific inhibition of mTORC2 activity on lung cancer cell invasion and metastasis. The central hypothesis is that RBD peptide preferentially suppresses invasion and metastasis in Rictor-amplified lung cancer. To test this hypothesis, two specific aims are planned: (1) establish that Rictor-amplified lung cancer cells are sensitive to migration and invasion suppression by RBD peptide via mTORC2-specific inhibition and (2) validate that mTORC2-specific inhibition by TAT-RBD peptide preferentially suppresses metastasis of Rictor-amplified lung cancer in mice. The success of the proposed study will not only prove the importance of mTORC2-specific inhibition on the invasion and metastasis in Rictor-amplified lung cancer, but also guide us to develop a therapeutic mTORC2-specific inhibitor by refining the RBD peptide as a therapeutic agent in the near future. Ultimately, the expected findings hold particular relevance for precision medicine, primarily with regard to lung cancer patients who present with Rictor amplification and thus could benefit from new selectively targeted treatment. This project is to address the LCRP Area of Emphasis: Identify innovative strategies for the treatment of lung cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110180
Entities
People
- Hsin-sheng Yang
Organizations
- United States Army
- University of Kentucky