A Chemical Proteomic Strategy for Mapping Codependency Pathways in KRAS-Driven Lung Cancer
Abstract
Background: Lung cancer is the leading cause of cancer-related cell deaths worldwide. In the U.S. alone, an estimated >154,000 Americans died from lung cancer in 2018. The single most prevalent form of lung cancer is lung adenocarcinoma, a type of non-small cell lung cancer and constitutes more than 80% of all lung malignancies. The most prevalent mutations in lung adenocarcinoma are in a gene that codes for the KRAS protein and this can drive cancer development. However, attempts to target this mutated protein has proven challenging and there are currently no therapeutic options in the clinic. An alternative therapeutic strategy is to identify treatments that do not directly target this KRAS, but rather other proteins that function to support KRAS. The proposed project describes a powerful strategy that identifies such potential therapeutic leads. Areas of Emphasis: The proposed studies address FY19 LCRP areas of emphasis, including: “identify innovative strategies for the treatment of lung cancer,” and “understand the molecular mechanisms of initiation and progression to clinically significant lung cancer.” Objective: Most systemic lung cancer chemotherapies are drugs that kill cancer cells. However, many of these drugs have side effects including toxicity against normal fast growing healthy cells (e.g., blood and hair) giving rise to a number of debilitating side effects. In the last decade, the paradigm for cancer chemotherapies has shifted from using systemic cytotoxic drugs to more selective, or "targeted", drugs that only affect cancer cells by targeting mutated proteins such as KRAS. Such targeted therapies are being shown to have fewer side effects than cytotoxic and have improved patient response rates, since therapies can be recommended only when the dysregulated protein target is detected. The discovery of future targeted therapies first requires identification of relevant protein targets and then another effort to develop drugs that affect these proteins to restore health. Although this may seem straightforward, there are significant obstacles that make this a challenging undertaking. For example, in efforts to identify molecules that selectively kill cancer cells it is notoriously difficult to identify what proteins these molecules are actually impacting, thereby hampering subsequent therapeutic development. To address this need, we have recently created a collection of multifunctional molecules in which each one is both drug-like and compatible with state of the art techniques used to detect and identify the target proteins. In this proposal, we aim to integrate our innovative drug-screening strategy with a specialized lung cancer model of KRAS-dependent tumor growth for the systematic identification of the protein targets that are selectively required in the tumor cells and dispensable for the survival of normal cells. To achieve these goals, we propose to (1) identify molecules that modulate cancerous behavior in lung cancer model systems, (2) use our advanced tools to systematically identify their protein targets, and (3) validate the role of these targets in lung cancer growth. We hypothesize that this innovative platform will lead to the discovery of new molecules that affect lung cancer biology and reveal details of the underlying mechanism(s) by which they work. This information can then be used to develop new, safer, targeted cancer therapies. Relevance to Service Members, Veterans, and Families: The goal of the proposed research is to develop tools, methods, and information that will directly benefit lung cancer patients. As smoking is the major cause for lung cancer, it impacts Service members and Veterans disproportionally. Indeed, numerous studies have shown that smoking, adverse health conditions, and mortality associated with smoking are significantly more prevalent among active military and Veterans compared to the general population. For example, the Veteran po
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010431
Entities
People
- Christopher G Parker
Organizations
- Scripps Research
- United States Army