Abstract 83: The role of Nrf2-Keap1 pathway in the survival of circulating metastatic cancer cells

Approximately 90% of all cancer deaths arise from the metastatic spread of primary tumors. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but they are the least well understood at the molecular level. As a barrier to metastasis, cells normally undergo an apoptotic process known as “anoikis,” in circulation. The recent technological advances in the isolation and characterization of rare circulating tumor cells (CTCs) will allow a better understanding of anoikis resistance. Detailed molecular and functional analyses of anoikis-resistant cells may provide insight into the biology of cancer metastasis and help identify novel targets for prevention of cancer dissemination. To uncover the molecular changes that govern the transition from a primary lung tumor to a secondary metastasis and specifically the mechanisms by which CTCs survive in circulation, we carried out whole-genome sequencing (WGS) of normal lung, primary tumors and the corresponding brain metastases from five patients with progressive metastatic NSCLC. We also isolated CTCs from patients with metastatic cancer and subjected them to whole-genome amplification and Sanger sequencing and quantitative digital PCR of genes of interest. While the primary tumors showed mutations in genes associated with cell adhesion and motility, brain metastases acquired mutations in adaptive and cytoprotective genes involved in the response to cellular stress such as Keap1, Nrf2 and E300, which are key players of the Keap1-Nrf2-ARE survival pathway. Nrf2 is a transcriptional factor that upon stress translocates into the nucleus, binds to the ARE (anti-oxidant response elements) and drives the expression of antioxidant genes. The identified mutations affect regulatory domains in all three proteins, suggesting a functional role in providing a survival advantage to CTCs in the peripheral blood, allowing their dissemination to distant organs.

Citation Format: Hashim M. Aljohani, John M. Furgason, Peter Amaya, Ayham Deeb, Jeffery J. Chalmers, El Mustapha Bahassi. The role of Nrf2-Keap1 pathway in the survival of circulating metastatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 83.