Targeting DCLK1 a Novel Regulator of DNA Damage Response in KRAS-Mutant Non-Small Cell Lung Cancer
Abstract
The objective of the proposed study is to target DCLK1, a kinase protein in KRAS mutant non-small cell lung cancer (NSCLC), as a potential therapeutic approach to reduce KRAS-driven resistance to cisplatin (chemo drug) and reduced tumor growth and metastasis. LCRP Areas of Emphasis 1. Identify innovative strategies for prevention and treatment of early and/or localized lung cancer and 2. Understand susceptibility or resistance to treatment. Basic Research Significance, Clinical Applicability, Timeline, and Benefits: KRAS mutant non-small cell lung cancer is undruggable. We found that knocking down DCLK1 reduced KRAS activity in tumor cells. The proposed basic research study will provide a definitive assessment of DCLK1 function in regulating the mutant KRAS and its associated oncogenic downstream targets in NSCLC. If successful, these studies will also provide further validation for targeting DCLK1 in the development of novel therapies aimed at the undruggable KRAS mutant non-small cell lung cancer. The basic research will determine the ability of DCLK1-targeted agents to reduce tumor growth and metastasis of KRAS mutant non-small cell lung cancer. Moreover, the basic research will determine if DCLK1-targeted agents can sensitize KRAS-mutant NSCLC to the chemotherapeutic agent cisplatin, potentially offering a desperately needed additional line of therapy for patients with advanced KRAS-mutant NSCLC. Patients with KRAS-mutant non-small cell lung cancer are benefitted by these studies. Patients with cisplatin-resistant non-small cell lung cancer also will benefit by these studies. The timeline is short (within 10 years) but very critical in developing DCLK1 targeting as an individual therapy and more importantly as an adjuvant therapy for human subjects. Basic research utilizing human cells and animal models are successfully leading to the development of agents to target DCLK1 in human cancers. The proposed study will advance the lung cancer field by helping us understand that the mutant KRAS can be regulated and targeted. It will advance the field toward developing a novel therapeutic target to inhibit DCLK1, a kinase protein and an upstream regulator of active KRAS in non-small cell lung cancer. It will advance the field toward understanding and developing novel strategies to target cisplatin resistant non-small cell lung cancer. Military Relevance: Lung cancer is the second leading cancer between veteran populations. Studies have indicated higher rates of lung cancer incidence and mortality among veterans than non-veterans. Veterans, by virtue of their work, are at high risk of developing lung cancer. Therefore, successful lung cancer treatment is a vital priority to veterans. The current proposal will determine the effect of DCLK1 targeting for effective treatment of KRAS mutant NSCLC. The outcome of the proposed work will lead to better clinical options for the effective treatment of untargetable KRAS mutant NSCLC, and will also help military healthcare providers improve the survival and quality of life of veterans and members of the military diagnosed with this devastating disease with KRAS mutation.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810457
Entities
People
- Parthasarathy Chandrakesan
Organizations
- United States Army
- University of Oklahoma Health Sciences Center