A Novel Approach to Co-Target KRAS and YAP in KRAS-Driven NSCLC
Abstract
Lung cancer is the leading cause of cancer death in the United States and worldwide. In non-small cell lung cancer (NSCLC), a protein called KRAS often becomes inappropriately turned on (becomes an oncogene) and causes tumor growth. The oncogenic change in KRAS is caused by a single-point mutation that allows KRAS to send signals to multiple molecular regulators of tumor progression. Patients with mutated KRAS lung cancer have a poor prognosis, and no current therapies are available to target this oncogene. It has been shown that KRAS is a useful therapeutic target, as its genetic ablation (gene deletion) in animal models is associated with impressive tumor regression. However, it was recently observed that tumor regression is actually transient. Over time, a new tumor progresses that is still devoid of KRAS, but is supported by a replacement oncogene called YAP. In the current project, we propose to investigate the hypothesis that both KRAS and YAP should be targeted to effectively inhibit KRAS mutant NSCLC. We propose to test this hypothesis by two approaches: genetic and pharmacological. In the genetic approach, we will engineer deletion of KRAS, YAP, or both KRAS and YAP genes in NSCLC cell lines, and determine cell growth capability in cell cultures or in xenograft mouse models that are permissible for growth of human tumors. In the pharmacological approach, we propose to combine two drugs, each with a specific targeting capability for either KRAS or YAP. Despite an intensive effort by leading research groups over a period of two decades, no effective pharmacological inhibitors of mutant KRAS have reached the clinic, feeding the perception that mutant KRAS is "undruggable." In a recent development, an experimental small molecule directed specifically at the mutation site of the KRAS protein demonstrated the ability to turn off its active status. This inhibitor has not yet been tested in any preclinical studies. YAP inhibitors have not yet been developed. Our preliminary studies determined that a heat-shock protein 90 inhibitor, ganetespib, which is already in clinical trials, is capable of arresting YAP nuclear activity that is required for its oncogenicity. We propose to combine these two small molecule inhibitors -- a mutant-specific KRAS inhibitor and ganetespib -- to co-target KRAS and YAP. We also propose to propagate Patient-Derived specimens in Xenograft mouse models (PDX) and determine their sensitivity to this combination of small molecule inhibitors of KRAS and YAP. The proposed studies are both conceptually and practically innovative: KRAS/YAP co-targeting in human KRAS mutant NSCLC has not been previously tested; the combination of the KRAS inhibitor with ganetespib is novel; and the inclusion of PDX experiments for the pharmacological treatment approach is both clinically relevant and innovative. The proposed studies have a high likelihood of not only determining the requirement for co-targeting KRAS and YAP in KRAS mutant NSCLC therapeutics, but will also help further development and translation of the proposed cytotoxic drugs to the clinic. Our studies address three of the Lung Cancer Research Program Areas of Emphasis: Identifying innovative strategies for treatment of localized lung cancer; understanding susceptibility of resistance to treatment; and understanding the molecular mechanism of progression to clinically significant lung cancer. The proposed research is highly relevant to current and past smokers among active duty military personnel and Veterans. Studies that have been performed over years have indicated higher rates of lung cancer incidence and mortality among Veterans. One of the reasons for the increased lung cancer rate is the higher smoking rate among Veterans as well as among active duty military personnel. The specific KRAS mutation in NSCLC targeted by the proposed pharmacological approach in our studies is the most common among KRAS mutant lung cance
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610213
Entities
People
- Hannah Rabinowich
Organizations
- United States Army
- University of Pittsburgh