Pancreatic cancer has no clear symptoms and there are no early detection methods available to screen for the presence of this deadly disease. Moreover, once pancreatic cancer is identified, limited treatment options and an insensitivity to chemotherapy result in a 5 year survival rate of ~5%. Clearly, new treatment options are urgently needed to extend the lives of pancreatic cancer patients. The vast majority of pancreatic cancers have mutations in the KRAS proto-oncogene, and while the idea of directly inhibiting mutant KRAS once held promise, to date, the many inhibitors developed to prevent mutant KRAS activity have had little success. We describe here, a novel oncogene named FAM83A that is a key activator of RAS-effector signaling (including MAPK and PI3K/AKT). Importantly, FAM83A is up-regulated by mutant RAS expression and is significantly elevated in pancreatic cancer tissue relative to normal pancreas. The identification of a novel oncogene capable of regulating the MAPK and PI3K/AKT pathways in cancer cells harboring mutant KRAS may provide an extraordinary opportunity for new, targeted therapies. Importantly, our preliminary data demonstrates that ablation of FAM83A expression in tumor-derived cells, including pancreatic cancer, inhibits cell growth and tumorigenicity and suppresses MAPK and PI3K/AKT signaling. The hypothesis of the current proposal is that a positive feedback loop is created by the RAS-mediated up-regulation of FAM83A and the FAM83A-mediated activation of MAPK and PI3K/AKT. To define the role of FAM83A in KRAS-mediated pancreatic cell transformation and examine whether the KRAS/FAM83A axis will serve as a therapeutic target in pancreatic cancer, the following specific aims have been developed.
In AIM 1 we will define the biological consequence and KRAS-mediated signaling changes that result from FAM83A suppression in pancreatic cancer cells. Using pancreatic cancer cells harboring mutant KRAS and elevated FAM83A, the biological consequence and changes in mutant KRAS-effector activation will be examined following FAM83A suppression.
In AIM 2 we propose to determine the RAS-effector signaling activated by aberrant FAM83A expression during pancreas duct epithelial cell (PDEC) transformation. Our proposed studies will define the importance of the positive feedback loop created by the KRAS-mediated up-regulation of FAM83A during PDEC transformation and the mechanism of FAM83A transcriptional induction by mutant KRAS and downstream RAS effectors. Understanding the interconnections between mutant KRAS, FAM83A, MAPK and PI3K/AKT will provide new insight into pancreatic cancer development and progression. Moreover, the novel KRAS/FAM83A feedback loop uncovered by this study may provide a unique therapeutic vulnerability for mutant RAS-expressing pancreatic cancer cells.
The successful identification of new proteins involved in promoting pancreatic cancer cell growth would provide an extraordinary opportunity for new, targeted therapies to help combat this devastating disease. We describe here the discovery of a novel oncogene named FAM83A that is required for the function of mutant KRAS, the key signal that drives the growth of 90% of all pancreatic cancers. Understanding how FAM83A promotes KRAS signaling will provide new insight into why pancreatic cancer cells divide uncontrollably and will set the stage for new therapies capable of targeting the KRAS/FAM83A interactions.
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