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You searched for +publisher:"University of North Carolina" +contributor:("Counter, Christopher"). One record found.

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University of North Carolina

1. Hayes, Tikvah. Targeting mutant KRAS in pancreatic cancer.

Degree: 2016, University of North Carolina

The development of pharmacologic inhibitors of the KRAS oncoprotein, which is mutated in ~30% of all human cancers, has been at the forefront of drug discovery for the last three decades. Despite intensive efforts by the pharmaceutical industry, no effective anti-KRAS strategies have reached the cancer patient. While many approaches to achieve this are being pursued, arguably inhibition of mutant KRAS effector signaling is considered the most promising to block KRAS-driven cancer growth. The best-validated downstream effector of KRAS is a three-tiered protein kinase cascade, the Raf-MEK-ERK protein kinase cascade, where KRAS activates Raf, which then activates MEK, and MEK then activates ERK. Activated ERK then activates a complex spectrum of signaling events that then drive cancer growth. Unfortunately, inhibitors of the first two levels, targeting Raf or MEK, have proven ineffective in mutant KRAS cancers. The ineffectiveness of anti-Raf and –MEK therapies has been attributed to inhibitor-induced resistance mechanisms, where the majority cause reactivation of ERK signaling to bypass the action of these inhibitors. Our studies sought to determine whether pharmacological inhibition of the last step at ERK will be more efficacious than treatment with either MEK or Raf inhibitors in mutant KRAS cancers. In our studies, we first determined that pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines by inducing both cycle cell arrest and apoptosis. Interestingly, we found that concurrent PI3K inhibition, another well-established KRAS effector, modulated ERK inhibitor sensitivity by enhancing the apoptotic phenotype. Next, we employed a drug sensitivity screen to identify novel inhibitor combinations that enhanced ERK inhibitor sensitivity. We identified the PI3K-AKT-mTOR signaling cascade as a potent modulator of ERK inhibitor sensitivity, which was consistent with our previous finding where concurrent PI3K inhibition combination enhanced ERK inhibitor sensitivity. We unexpectedly found that long-term treatment of sensitive cell lines caused cellular senescence, a type of irreversible growth arrest, mediated in part by causing degradation of Myc and activation of the p16-RB tumor suppressor pathway. Next, we performed a novel genetic gain-of-function screen to identify mechanisms of acquired resistance to ERK inhibition. Interestingly, we identified, once again, the PI3K-AKT signaling cascade, as modulator of ERK inhibitor sensitivity. We also found p38 to be an important modulator or ERK inhibitor sensitivity. Finally, to investigate de novo resistance to ERK inhibition, we used a loss-of-function screen to identify kinases whose inhibition in combination with ERK inhibitor treatment resulted in sensitivity. Future studies will be needed to elucidate the mechanisms behind these modulators of pharmacological ERK inhibition. Collectively, our findings not only revealed distinct consequences of inhibiting this kinase cascade at the level of ERK, but identified… Advisors/Committee Members: Hayes, Tikvah, Der, Channing, Baldwin, Albert, Counter, Christopher, Johnson, Gary, Kim, William.

Subjects/Keywords: School of Medicine; Curriculum in Genetics and Molecular Biology

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APA (6th Edition):

Hayes, T. (2016). Targeting mutant KRAS in pancreatic cancer. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:f816a0b0-3d43-4afb-9623-dcbfb1d7bd39

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Hayes, Tikvah. “Targeting mutant KRAS in pancreatic cancer.” 2016. Thesis, University of North Carolina. Accessed September 27, 2020. https://cdr.lib.unc.edu/record/uuid:f816a0b0-3d43-4afb-9623-dcbfb1d7bd39.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Hayes, Tikvah. “Targeting mutant KRAS in pancreatic cancer.” 2016. Web. 27 Sep 2020.

Vancouver:

Hayes T. Targeting mutant KRAS in pancreatic cancer. [Internet] [Thesis]. University of North Carolina; 2016. [cited 2020 Sep 27]. Available from: https://cdr.lib.unc.edu/record/uuid:f816a0b0-3d43-4afb-9623-dcbfb1d7bd39.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Hayes T. Targeting mutant KRAS in pancreatic cancer. [Thesis]. University of North Carolina; 2016. Available from: https://cdr.lib.unc.edu/record/uuid:f816a0b0-3d43-4afb-9623-dcbfb1d7bd39

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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