UCLA

Pancreatic ductal adenocarcinoma (PDAC), which comprises 90% of all human pancreatic cancers, is a devastating disease with overall 5-year survival rate of only 5%. A major challenge is to identify novel targets and develop strategies for its treatment. New approaches will most likely arise from a detailed understanding of the molecular signaling pathways that stimulate the unrestrained proliferation of these cells. The PI3K/AKT/mTOR pathway plays a pivotal role in pancreatic cancer. Several drugs, including mTOR kinase inhibitors, are in development to target this pathway. In addition to growth-promoting signaling, the mTORC1/S6K axis also mediates negative feedback loops that restrict signaling via insulin/IGF receptor and other tyrosine kinase receptors and can lead to drug resistance. In this dissertation, I describe studies performed in PDAC cell lines using different inhibitors of the mTOR pathway, including: a) rapamycyn, an allosteric mTOR inhibitor; b) PP242 and KU63794, active-site mTOR inhibitors; c) NVP-BEZ235, GDC-0980 and PKI-587, dual PI3K/mTOR inhibitors, d) metformin and berberine, two anti-diabetics drugs with emerging promising anti-cancer properties. We show that active-site mTOR and dual PI3K/mTOR inhibitors induce an unexpected increase in the activity of the ERK pathway in PDAC cells. Additionally, we demonstrate that ERK over-activation can be abrogated by the use of MEK inhibitors. We also show that metformin and berberine are capable of inhibiting mTOR signaling without ERK over-activation. Our mechanistic studies demonstrate that dual PI3K/mTOR inhibitors suppress a novel PI3K-independent negative feedback loop mediated by mTORC2 thereby leading to enhancement of MEK/ERK pathway activity in pancreatic cancer cells. Finally, we review negative feedback mechanisms that restrain signaling via upstream elements of the PI3K/AKT/mTOR pathway as well as mechanisms leading to the compensatory activation of other pro-oncogenic pathways, including MEK/ERK. Taken together, the data presented in this dissertation have important translational applications and provide a rationale for the study of combinatory target therapy in pancreatic cancer.