Investigating Cooperation between KEAP1 and LKB1 Inactivation in Lung Adenocarcinoma
Abstract
Lung cancer is responsible for more cancer-related deaths than any other malignancy worldwide, and members of the Armed Forces are almost twice as likely to develop lung cancer as non-military individuals. The majority of lung cancers are classified as lung adenocarcinomas (LA). Studies of patient LA tumors have revealed that 30%-90% of LAs have genetic mutations that inactivate the Liver Kinase B1 (LKB1) protein and mutations to LKB1 correlate with poor patient survival. Inactivation of LKB1 allows for accelerated growth of LA cancer cells, but, paradoxically, alters the metabolism of LA cancer cells that hinders growth and can cause cell death. How lung cancers blunt these negative effects of LKB1 inactivation while simultaneously taking advantage of loss of LKB1 s inhibition of growth remain unclear. In cancer cells, the protein Nrf2 functions as an oncogene, allowing tumor cells to adapt their metabolism to allow for unrestricted growth and resist chemotherapy. The KEAP1 protein normally prevents Nrf2 activity; however, mutational inactivation of KEAP1 results in excessive Nrf2 activity. As such, inactivating mutations to KEAP1 are a common feature of tumors. Interestingly, inactivating mutations to KEAP1 and LKB1 frequently occur together in LA cancer tumors. Based upon these observations, our project will test whether inactivation of KEAP1 cooperates with LKB1 inactivation in LA to provide Nrf2-mediated adaptations to cancer cell metabolism and allow unfettered growth and survival and resistance to chemotherapy. LKB1 inactivation is present in almost 90% of patients with LA, and as evidenced by recent studies, these patients face overwhelming hurdles for successful treatment. Completion of this study will provide clarity into how lung cancer cells balance the negative effects of LKB1 inactivation, while utilizing the growth advantages associated with LKB1 loss, as well as to how LA tumors with inactive LKB1 develop resistance to therapy, areas of LA biology still poorly understood. While the primary goals of this project will not have immediate clinical impact, both the data and tools developed from this work will enable future studies geared towards clinical application of our findings. In particular, this work will also contribute necessary information to aid the design of therapies that target LA with LKB1 inactivation. Currently efforts are underway to develop treatments specific for LKB1 inactive LA; however, based upon the incidence of KEAP1 inactivation in LA, there is considerable potential that these developing therapies may lack the necessary efficacy due to KEAP1 mutations. In parallel are efforts to develop inhibitors to Nrf2 for use as chemotherapies. As such, the data resulting from this project would indicate that application of Nrf2 inhibitors in conjunction with LKB1 targeted therapies or standard therapies would have increased efficacy in LA harboring LKB1 and KEAP1 inactivating mutations. Thus, there is considerable potential that this work will immediately influence the clinical development of these therapies and could in fact lead to new treatment approaches for patients within next few years. In sum, this study will allow us to define a cooperative relationship between LKB1 and KEAP1 inactivation in non-small cell lung cancer tumorigenesis and acquire the necessary data to meet our long-term goals of identifying the molecular mechanisms of progression to clinically significant lung cancer and therapeutic resistance, both of which are areas of emphasis for the Lung Cancer Research Program.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610201
Entities
People
- Landon Inge
Organizations
- United States Army