Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with a poor prognosis and limited treatment options. Pancreatic ductal adenocarcinoma (PDAC) accounts for the greatest number of these cases. The gene KRAS is mutated in greater than 95% of PDAC cases, and this leads to the activation of the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway. Substantial experimental evidence implicates the key role of this protein kinase cascade in driving KRAS-dependent PDAC growth. Despite this importance, the mechanisms by which ERK drives PDAC growth remain surprisingly unresolved. At every level of the Ras-Raf-MEK-ERK cascade there are structurally and functionally related isoforms. There is now strong evidence for striking differences in the role of different Ras and Raf isoforms in signaling and cancer. Whether this is also the case for the two highly related ERK1 and ERK2 isoforms, which share 84% sequence identity, remains underexplored. Much of our current understanding of ERK biological function comes from studies on ERK1/2 that did not distinguish between these two isoforms. In addition, ERK1/2 are capable of phosphorylating greater than 200 known substrates, but there is little understanding of which of these substrates are important drivers of the ERK/MAPK pathway. The extensive list of substrates causes further complexity for studies regarding which substrates play an active role in the development and maintenance of pancreatic cancer. Based on some reports in the literature suggesting that ERK1 and ERK2 may play different roles in certain circumstances, I performed preliminary studies to determine whether these two isoforms are interchangeable in PDAC. My studies using shRNA directed against ERK1 or ERK2 in a panel of 10 PDAC cell lines showed that loss of ERK1 or ERK2 reduced both anchorage-dependent clonogenic growth and anchorage-independent soft agar growth, indicating that neither of these highly related isoforms can compensate functionally for the loss of the other. Therefore, I hypothesize that ERK1 and ERK2 have distinct and nonredundant roles in driving KRAS-mutant pancreatic cancer growth. I propose three specific aims to test my hypothesis: I will (1) define the dependency of KRAS-mutant PDAC growth on ERK1 and ERK2; (2) define ERK1 and ERK2 roles in PDAC epithelial to mesenchymal transformation, invasion and metabolic alterations; and, (3) Identify ERK isoform-dependent substrates in PDAC. These studies will investigate the divergent and shared functions of ERK1 and ERK2 in pancreatic cancer and have the potential to discover novel signaling mechanisms of this critical node in the ERK MAPK pathway. This fellowship will also enhance my research skills, establish a firm foundation in basic and translational cancer biology and help develop my skills to become an independent investigator in cancer research.
Pancreatic cancer is the fourth leading cause of cancer deaths within the United States, and with poor prognosis and few treatment options, almost all patients pass away from the disease. Currently, the standard of treatment shows little efficacy against the disease leaving a need for new potential therapeutic targets. My preliminary studies into the role of ERK1 and ERK2 in pancreatic cancer show a role for the kinases in the growth of the cancer, while also showing that one isoform cannot compensate for the loss of the other. I plan to study the differential role of ERK1 and ERK2 in both the development and maintenance of KRAS mutant pancreatic cancer, with the goal of characterizing the isoforms for potential therapeutic intervention.
|Ryan, Meagan B; Finn, Alexander J; Pedone, Katherine H et al. (2016) ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma. Mol Cancer Res 14:1009-1018|
|Ryan, Meagan B; Der, Channing J; Wang-Gillam, Andrea et al. (2015) Targeting RAS-mutant cancers: is ERK the key? Trends Cancer 1:183-198|