Dissertations, Theses, and Capstone Projects

Date of Degree


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David A. Foster

Committee Members

Patricia Rockwell

Olorunseun Ogunwobi

Anjana Saxena

Saghi Ghaffari

Subject Categories



Cancer cells require nutrient uptake for anabolic reactions needed for cellular growth and proliferation. The mammalian target of rapamycin (mTOR) is a key regulator of cellular growth that links nutrient availability and growth factor signals. mTOR mediated signaling pathways are often dysregulated in a wide range of cancers. We previously reported that KRas-driven cancer cells sense exogenous lipids via de novo production of phosphatidic acid, which ultimately activates both mTOR complexes – mTORC1 and mTORC2. Activated mTORC2 phosphorylates the survival kinase Akt at Ser 473 which is required for full Akt activation. A direct substrate of Akt and a major lipogenic enzyme is ATP citrate lyase (ACLY). We demonstrate here that exogenously supplied oleic acid (OA) induces ACLY phosphorylation at the Akt site in an mTORC2-dependent manner. Increased ACLY activity diverts citrate out of the mitochondria where it can be used for anabolic reactions rather than the catabolic reactions of the TCA cycle. Additionally, inhibition of ACLY resulted in loss of cell viability in the absence of glutamine (Gln) in KRas-driven cancer cells. While cells were sensitive to Gln deprivation by itself, ACLY inhibition increased cytotoxicity. Cells harboring KRas mutations acquire a dependence on Gln and utilize Gln via glutaminolysis to generate the TCA cycle intermediate α-ketoglutarate. A pan-transaminase inhibitor aminooxyacetate (AOA) interferes with Gln metabolism in KRas-driven cancer cells. Inhibiting Gln utilization with AOA was minimally toxic by itself; however, AOA combined with ACLY inhibition led to apoptotic cell death. Non-transformed BJ-hTERT human fibroblasts or MCF7 breast cancer cells that have wild type KRas did not show any change in viability. These data reveal a synthetic lethality between pharmacological inhibition of Gln utilization and ACLY inhibition that is specific for KRas-driven cancer cells. Thus, there is an apparent metabolic reprograming in KRas-driven cancer cells that could be exploited therapeutically in what is likely around 30% of human cancers, which harbor KRas mutations.

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