Validating USP27X as a Drug Target in Lung Cancer
Abstract
In order to properly respond to external stimuli, the cells in our body utilize a variety of biochemical pathways to interpret cues they receive from the environment and make decisions, for example to start or stop dividing, migrate, or even trigger mechanisms for self-destruction. These complex signaling cascades start with receptors, which are localized on the cell surface and are responsible for capturing the right signals. One such class of receptors are the so-called receptor tyrosine kinases (RTKs), which receive messages at the cell membrane and convey them to the cell by phosphorylating different proteins in the cytoplasm. RTKs have important roles in many processes, from regulation of embryonic development to the maintenance of adult tissue homeostasis. Regrettably, the functions of these receptors are often perturbed in cancer, where their abnormal activation potentiates tumor progression and metastasis. A classic example of this phenomenon is the overexpression of Epidermal Growth Factor Receptor (EGFR). Overexpression and activation of this receptor is crucial for lung cancer growth. Several anti-cancer therapies have been developed to bind to EGFR and block its activity. Unfortunately, however, these therapies are not durable; by overexpressing EGFR or making small changes in its structure, cancer cells can avoid the negative effects of these targeted agents. Therefore, a new therapy that leads to destruction of EGFR in cancer cells would be much more promising in the battle against lung cancer. In his recent studies, Dr. Atanassov discovered a novel, previously uncharacterized deubiquitinating enzyme (DUB), USP27X, whose functions are required to support the overexpression of several RTKs, including EGFR, in cancer cells. Ablation of this DUB leads to a striking reduction of the levels of these RTKs and severe tumor growth impairment in experimental tumor models. Thus, Dr. Atanassov s studies aim to define the molecular mechanism underlying the impaired growth of USP27X depleted tumors, which is a topic for FY20 LCRP, and establish USP27X as a novel target in cancers where RTK overexpression or mutation drives progression. Aberrations in RTK pathways are directly involved in development and progression of many cancers. The biggest challenges to clinical utility of current RTK targeted therapeutics are primary or acquired treatment resistance. Hence, identifying new molecular targets in RTK-driven therapy-resistant cancers is imperative. As a deubiquitinase, USP27X is a druggable enzyme and Dr. Atanassov studies will illuminate new avenues for therapeutic intervention. Together, the results obtained from the proposed project will determine whether USP27X is a valuable therapeutic target in lung cancer. Dr. Atanassov s career goal is to become a leader in innovation in the field of experimental therapeutics by establishing a laboratory that serves to bridge the gap between basic scientific discoveries and the realities that physicians and patients face daily in the clinical setting. In this regard, the proposed studies for this Career Development Award will be greatly assisted by the exceptional team of mentors and collaborators including Drs. Herberger, Goodrich, and Seshadri. Dr. Hershberger is a Co-Director of the Lung Translational Research Group at Roswell Park Comprehensive Cancer Center and an outstanding scientist with an established record of productivity in the study of lung cancer prevention and treatment. She will not only provide Dr. Atanassov with crucial guidance, but will also connect him to additional resources he may need as his project develops (including new lung cancer models, patient biospecimens, tissue microarrays, or data sets) and provide him with the opportunity to present his work to our lung cancer research community. Both members of the mentoring team, l be an immense help for Dr. Atanassov in his research aims and will help him make high-i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110647
Entities
People
- Boyko Atanassov
Organizations
- United States Army