Noncanonical Role for Phosphoserine Aminotransferase 1 (PSAT1) in Promoting EGFR-Mutant Lung Cancer Metastasis
Abstract
Rational for Proposed Research: Despite advances in screening and new treatment options, 150,000 individuals will die of lung cancer this year in the United States alone. While survival rates are generally good in those patients diagnosed with early-stage disease, advanced-staged patients have significantly reduced mortality. These statistics suggest that patients succumb to their disease due to the spreading or metastasis to other organs within the body. A substantial amount of research has highlighted certain pathways that are involved in the growth of primary tumors within the lung. However, the cellular factors that allow for tumor metastasis are still not fully understood. Therefore, identifying new processes that promote metastatic spreading directly addresses the Lung Cancer Research Program Area of Emphasis for increased understanding of the molecular mechanisms of initiation and progression to clinically significant lung cancer. We have recently found that high expression of a metabolic protein, called PSAT1, negatively impacts the survival of lung cancer patients whose tumors are specifically driven by genetic mutations that abnormally activate growth signals from the epidermal growth factor receptor (EGFR-mutant). Unexpectedly, we observed that decreased expression of PSAT1 led to inhibition of the motility of these cancer cells and that the traditional activity of PSAT1 in cell metabolism may not be required for this effect. These findings suggest that an alternative function of this protein contributes to EGFR-mutant lung cancer metastasis. The objective of the proposed research is to confirm the mechanism(s) by which PSAT1 promotes cell metastasis and to identify the downstream cellular factors. These studies will be performed in relevant systems generated directly from patient tumors and in appropriate assays that assess metastatic capability, particularly within animal models. Ultimate Applicability for Proposed Research: Lung cancer patients ultimately die from metastatic spread within the body. As conventional therapies against lung cancers tend to target pro-growth activities, these agents ultimately fail as patients progress towards metastatic disease. Therefore, new therapeutic strategies aimed at blocking metastasis may have significant impact on patient mortality. For this, new research is essential in identifying cellular processes that may be useful targets in these approaches. While the proposed research is not immediately clinically applicable, the outcomes will validate the relevance of new cellular targets and advance our understanding of processes that drive lung cancer metastasis. The work in this application intends to provide the foundation to support the inhibition of PSAT1 as an anti-metastatic therapy. Further, the requirement of a non-traditional function of PSAT1 suggests that blocking this activity may be more selective against tumors and lead to lower toxicities than more conventional treatments. Improvements in drug development technologies, such as computational modeling, have drastically reduced the time necessary from target discovery to clinical applicability, meaning that drugs specifically designed against the pro-metastatic function of PSAT1 could be clinically relevant in the near future. Lung cancer has numerous underlying causes, including both genetic and those arising from environmental exposures. While lung cancers driven by EGFR-mutations are generally observed in nonsmokers, tobacco use at an earlier age reduces the overall survival in patients diagnosed with EGFR-mutant lung tumors. As the military traditionally has higher rates of smoking and predominantly consists of young individuals between 20 and 30 years of age, military personnel with this disease may be disproportionately affected. In addition, statistics indicate that the ethnic diversity within the military is continually increasing, including those of Asian and Hispanic descent.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910445
Entities
People
- Brian Clem
Organizations
- United States Army
- University of Louisville