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Understanding the Role of Group I PAKs in Thyroid Cancer

Knippler, Christina Michelle
http://rave.ohiolink.edu/etdc/view?acc_num=osu1561469174472671

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Thyroid cancer incidence has been increasing over the last several decades. Most thyroid cancers are curable, however, aggressive tumors do not respond to standard therapy and have only limited responses to recently-approved targeted therapies, especially when metastatic cancer is present. Many "driver" mutations of thyroid cancer have been determined, but it is becoming increasingly clear that these oncogenic pathways do not act as singular entities to "drive" malignancy. It is, therefore, pivotal to understand the complexity of thyroid cancer signaling in order to determine the best therapeutic approach. The MAPK pathway is overactivated in the majority of thyroid cancers, with the most common mutation causing the valine to glutamic acid point mutation at amino acid 600 in the kinase BRAF (i.e. BRAF V600E). Members of the MAPK pathway, and in particular BRAF V600E, are therapeutic targets of high interest, with ongoing clinical trials using pathway inhibitors. Preliminarily, these drugs result in only partial responses and resistance. Research is ongoing to determine the mechanisms of innate and acquired resistance to these drugs. Our prior research has identified a family of serine/threonine kinases, the group I p21-activated kinases (PAKs), as a novel indicator of aggressive characteristics in thyroid cancer. PAK1 protein levels and activation are highly expressed in the invasive edges of thyroid cancers, compared to the center of the tumor or normal thyroid tissue. BRAF and PAK1 signaling are interconnected, both necessary for thyroid cancer migration, with PAK activation in vitro and in vivo regulated by BRAF expression. Further, BRAF and PAK1 physically interact. Therefore, the connection between BRAF and PAK1 are significant for thyroid cancer progression. The objective of the current work was to characterize the BRAF-PAK1 interaction in order to develop novel therapeutic approaches. This research determined the ability of PAK1 to be pharmacologically inhibited and tested the hypothesis that group I PAK inhibitors would reduce thyroid cancer growth and motility- two important hallmarks of cancer progression. Biochemical approaches tested how PAK1 physically interacts with BRAF, and its constitutively active mutated form, BRAF V600E. We hypothesized that PAK1 and BRAF physically interact as a complex with other mediating proteins and that these proteins provide additional targets for better therapeutic efficacy. This work utilized both in vitro and in vivo models to provide a comprehensive understanding of the BRAF and PAK1 complex. In vitro studies using several different thyroid cancer cell lines determined that group I PAKs could be pharmacologically inhibited and this reduced thyroid cancer cell growth, induced cell cycle arrest, and reduced cell invasion. Further, PAK inhibition could be combined with BRAF V600E and AKT inhibition for further synergistic reductions on thyroid cancer cell growth, useful for future clinical application. Importantly, group I PAK inhibition was effective in vivo in a mouse model of thyroid cancer where BRAF V600E was overexpressed in the thyroid. PAK inhibition restricted thyroid size and also carcinoma formation. In vitro biochemical approaches determined that both wild-type BRAF and BRAF V600E can physically interact with PAK1 in precise cell contexts, most often during mitosis. The interaction is unlikely to be direct, but may be facilitated through part of the PAK1 regulatory domain and does not require PAK1 kinase function. Proteomic evidence suggests that this interaction is mediated by chaperone proteins, allowing BRAF and PAK1 to interact transiently. These studies expand our understanding of the signaling crosstalk between BRAF and PAK1 and identify the group I PAKs as therapeutically targetable kinases in thyroid cancer. This provides further evidence to continue efforts in drug development targeting the group I PAKs, as well as potential combination strategies with BRAF, AKT, and possibly HSP90 inhibitors, for patients with aggressive thyroid cancers.
Matthew Ringel, MD (Advisor)
David Carbone, MD, PhD (Committee Member)
Joanna Groden, PhD (Committee Member)
Michael Ostrowski, PhD (Committee Member)
Mark Parthun, PhD (Committee Member)
162 p.
Biomedical Research

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Citations

  • Knippler, C. M. (2019). Understanding the Role of Group I PAKs in Thyroid Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1561469174472671

    APA Style (7th edition)

  • Knippler, Christina. Understanding the Role of Group I PAKs in Thyroid Cancer. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1561469174472671.

    MLA Style (8th edition)

  • Knippler, Christina. "Understanding the Role of Group I PAKs in Thyroid Cancer." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1561469174472671

    Chicago Manual of Style (17th edition)

osu1561469174472671
153
© 2019, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.