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    Ashley Martel Zehnder.
    Targeting cancer cells while sparing normal cellular function is the elusive target of all cancer researchers. The ERK1/2 MAPK pathway is critical for cellular survival and over 30% of all human cancers have mutations or altered expression of these pathway members. Two cancers are particularly dependent on this pathway for survival, melanoma (~60% BrafV600E mutations) and pancreatic cancer (> 90% KrasG12D mutations). Our previous work describes the identification of an ERK1/2 MAPK scaffold, IQGAP1, that appears to function in a tumor-specific fashion and is not required for normal cellular function. However, it is unclear how targeting this scaffold-kinase interaction will affect tumorigenesis in-vivo as well as how it will affect the ERK1/2 MAPK pathway downstream. The work in this thesis expands previous in-vitro validation of IQGAP1 as a cancer specific target by characterizing tumor response in the context of PLX4032 resistance in melanoma as well as in mouse models of pancreatic cancer. Our work also identifies a key alteration in the phosphorylation of the linker region of SMAD2 downstream of TGFβ when IQGAP1 is depleted or targeted therapeutically. This has important consequences for tumor behavior as well as changes in the extracellular matrix within tumors, which could make tumors more invasive and resistant to therapy. We additionally examine the validity of IQGAP1 as a therapeutic target in canine melanoma, an alternative model of melanoma that recapitulates many of the characteristics of human melanoma, but in a Braf and Nras wild-type setting. Through this work, we have improved the understanding of the relationship between ERK1/2 and TGFβ pathways in cancer as well as paved the way for additional clinical development of this novel cancer therapeutic.
    Digital Access   2015