Investigating A Tumor Suppressor Role For Parkinson'S Susceptibility Gene Lrrk2 In Lung Cancer

In this study we investigate a novel and previously untested research question: does a known disease susceptibility gene in Parkinson9s disease (PD) also act as a tumor suppressor gene in lung cancer? Our screen of publicly available cancer patient sequence data for genome and transcriptome alterations of genes that modulate autophagy, an important tumor cell survival process, revealed a dramatic loss of gene expression of Leucine-rich repeat kinase 2 (LRRK2) in non-small cell lung tumors compared to matched normal tissue. We further confirmed reduced or absent LRRK2 protein expression in a panel of lung cancer cell lines. Activating kinase-domain mutations in LRRK2 and their effect on autophagy in neuronal cell types is under study in PD; however, the pathological role of altered LRRK2 in cancer and its effect on autophagy status and tumorigenicity is completely unexplored. Pharmacological inhibition of the LRRK2 kinase domain was recently shown to stimulate autophagy in PD cell lines, while many tumors are thought to exploit elevated autophagy to survive metabolic stress and chemotherapy. Ongoing clinical trials are testing combination autophagy inhibition with current standard of care treatments in multiple cancers. Therefore, a better understanding of pathogenic LRRK2-mediated autophagy in lung cancer could form the basis of a new approach to help identify lung cancer patients that may benefit from treatment strategies employing autophagy inhibitors. Our preliminary data indicates that LRRK2 knockdown in lung cancer cell lines leads to altered cellular phenotypes and increased protein levels of a known lung cancer gene. We are further testing whether genetic and/or pharmacological inhibition of LRRK2 facilitates tumorigenesis in standard murine models of lung cancer. Our investigation of the biological relevance and therapeutic potential of a surprising discovery linking neurodegenerative disease-associated LRRK2 and lung cancer may uncover a new tumor suppressor gene and provide a novel marker (i.e. LRRK2 loss) to aid in lung cancer detection. Citation Format: Chandra Lebovitz, Norman Chow, Wan Lam, Sharon Gorski. Investigating a tumor suppressor role for Parkinson9s susceptibility gene LRRK2 in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3668.