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ucin1318610225.pdf (8.29 MB)
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Modifiers of Ras-driven Tumorigenesis and Therapeutic Response
Author Info
Stengel, Kristy R.
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318610225
Abstract Details
Year and Degree
2011, PhD, University of Cincinnati, Medicine: Cell and Molecular Biology.
Abstract
The Ras oncoprotein is a key mediator of mitogenic signaling. Gain-of-function Ras mutations are observed in as many as 30% of human cancers, consistently extensive effort has been made to develop Ras-specific cancer therapies. Traditionally, Ras itself has not been considered a tractable target for small molecule intervention, therefore development of Ras-targeted therapies have focused on inhibition of Ras effector molecules such as the Raf and Phosphatidylinositol 3’OH kinases. Clinical results with such inhibitors have been largely disappointing. For instance, Raf inhibitors actually activate ERK signaling, sensitivity of Ras mutant cells to MEK inhibitors is variable and clinical studies have uncovered toxicities that may limit their use, while PI3K inhibitors are ineffective as single agents in pre-clinical models. Further complicating the issue is the realization that Ras addiction may not simply be determined by the presence of an activating Ras mutation, rather other lesions within the cell may modulate sensitivity to Ras withdrawal. Therefore, the current setbacks in the development of Ras-targeted therapies highlight the need to: (1) stringently define the molecular contexts in which Ras-mutant cancers are and are not sensitive to available Ras-targeted therapies such as MEK inhibitors and (2) continue to identify novel targets for therapeutic intervention in tumors driven by Ras mutation. Here, we describe the mechanistic function of the cell cycle regulator, RB, and discuss how disruption of RB-mediated checkpoints can modify the response of Ras-transformed cells to both cytotoxic and Ras-targeted therapies. While RB deletion sensitizes Ras-transformed cells to the effects of the DNA-damaging therapy, Camptothecin, RB-deficient cells display relative insensitivity to Ras-targeted therapies. In all, these studies suggest that RB status diminishes therapeutic response to Ras-targeted agents and should be evaluated when considering treatment with such agents. These studies further highlight the necessity for the continued identification of Ras-specific therapeutic targets. Cdc42 is a Ras-related small GTPase that has been implicated in oncogenic signaling. Here, we demonstrate a requirement for Cdc42 in Ras-mediated transformation and tumorigenesis. Deletion of Cdc42 dramatically alters the cell morphology and inhibits the growth of Ras-transformed cells, while non-transformed cells and c-Myc transformed cells are largely unaffected. Furthermore, loss of Cdc42 expression correlated with reduced Akt signaling, restoration of which partially rescued the proliferation defects associated with Cdc42 loss. Finally, disruption of Cdc42 function in established tumors inhibited continued tumor growth; highlighting both the importance of Cdc42 for HRasV12-driven tumor maintenance and the possibility that therapeutic targeting of Cdc42 may be of benefit in Ras-driven malignancies.
Committee
Yi Zheng, PhD (Committee Chair)
Robert Brackenbury, PhD (Committee Member)
Sohaib Khan, PhD (Committee Member)
Erik Knudsen, PhD (Committee Member)
Susanne Wells, PhD (Committee Member)
Pages
133 p.
Subject Headings
Cellular Biology
Keywords
Ras
;
small GTPase
;
RB
;
cell cycle
;
targeted therapy
;
Cdc42
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Citations
Stengel, K. R. (2011).
Modifiers of Ras-driven Tumorigenesis and Therapeutic Response
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318610225
APA Style (7th edition)
Stengel, Kristy.
Modifiers of Ras-driven Tumorigenesis and Therapeutic Response.
2011. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318610225.
MLA Style (8th edition)
Stengel, Kristy. "Modifiers of Ras-driven Tumorigenesis and Therapeutic Response." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318610225
Chicago Manual of Style (17th edition)
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Document number:
ucin1318610225
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Copyright Info
© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.