SOS2 Is a Tractable Therapeutic Target to Limit Therapeutic Resistance in Non-Small Cell Lung Cancer
Abstract
Scientific Objective and Rationale: Lung adenocarcinoma is the leading cause of cancer death. Traditional chemotherapeutic treatment of lung cancer has involved using nonspecific cytotoxic drugs that (hopefully) harm the rapidly growing tumor cells to a greater extent than their normal surroundings. However, new treatments now focus on identifying and then targeting those intracellular signals that specifically drive tumor growth and survival. For 75% of lung adenocarcinomas, these intracellular driver signals involve components of one particular signaling pathway that originates at a cell-surface receptor known as epidermal growth factor receptor (EGFR) and signal to its downstream components, including the oncogene KRAS. Multiple different therapeutics that target specific components of this EGFR/KRAS signaling pathway have been Food and Drug Administration (FDA)-approved to treat subsets of patients that have specific mutations within the EGFR/KRAS pathway. Unfortunately, both intrinsic resistance to certain therapeutics and acquired resistance once therapy has begun has limited the overall effectiveness of these drugs. Therefore, identifying other therapeutic targets that can help overcome therapeutic resistance holds enormous therapeutic promise. This proposal tests one such target, the protein SOS2, which is central to signaling from EGFR to the oncogene KRAS. Based on our preliminary data, we hypothesize that inhibiting SOS2 will limit therapeutic resistance in EGFR- and KRAS-mutated non-small-cell lung cancers (NSCLCs). The major objectives of this proposal are to (1) understand the mechanisms of resistance to treatment with FDA-approved EGFR/KRAS pathway inhibitors in EGFR- and KRAS-mutated NSCLC cell lines and (2) identify innovative treatment strategies that will help overcome this therapeutic resistance (Areas of Emphasis for the LCRP). Ultimate Applicability of the Research: Driver mutations in the EGFR/KRAS pathway members are found in three quarters of lung adenocarcinomas. Successful targeting of this pathway would be a major advancement in the treatment of a majority of lung cancer patients and have the potential to significantly eradicate deaths from lung cancer. This proposal uses lung cancer cell lines to test whether an integral member of this signaling pathway, the protein SOS2, is a viable therapeutic target whose inhibition would limit resistance to FDA-approved targeted therapies used to treat lung adenocarcinoma. From the research outlined in this proposal, we expect to know whether SOS2 inhibition can limit therapeutic resistance in EGFR- and KRAS-mutated lung adenocarcinomas, two molecular subtypes of lung adenocarcinoma that account for 40-50% of NSCLCs. Since a number of academic laboratories and drug companies are currently designing compounds that can target SOS2 and its closely related family member, SOS1, these studies could be rapidly translated into new clinical trials within the next 5e to 10 years. In addition to testing SOS2 as a target to limit resistance, we propose developing and characterizing cellular models of EGFR inhibitor resistance that will be critical tools for understanding therapeutic resistance and then characterizing a strategy to inhibit this resistance using genomic tools. Military Relevance: U.S. military members and Veterans are at an increased risk of developing KRAS-mutated lung cancer due to higher smoking rates. Furthermore, exposures of our Service members and Veterans to asbestos, ionizing radiation, industrial pollutants, diesel exhaust, and Agent Orange, as well as exposures of Veterans of Iraq and Afghanistan to burn pits, are risk factors to developing both EGFR- and KRAS-mutated lung cancer. Therefore, understanding the molecular mechanisms of resistance to treatment with targeted therapeutics and identifying SOS2 inhibition as an innovative strategy for prevention and treatment of lung cancer will have a particularly profound impact
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910590
Entities
People
- Robert L Kortum
Organizations
- Uniformed Services University of the Health Sciences
- United States Army