Graduation Year

2015

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Cell Biology, Microbiology, and Molecular Biology

Major Professor

Keiran Smalley, Ph.D.

Committee Member

Geoffrey Gibney, MD.

Committee Member

Eric Haura, MD.

Committee Member

Conor Lynch, Ph.D.

Committee Member

Alvaro Monteiro, Ph.D.

Keywords

Cellular signaling, EphA2, HSP90, MAPK, Phosphoproteomics, PTEN

Abstract

In the last four years, seven new drugs have been FDA approved for the treatment of late stage melanoma, for the field of melanoma, this marks an incredibly exciting. Three of these new therapies, vemurafenib, dabrafenib and trametinib are small molecule kinase inhibitors that target the MAPK pathway and as such have been approved for the treatment of BRAFV600 mutant melanomas. Yet despite recent advances, mechanisms of intrinsic and acquired BRAF inhibitor resistance continue to undermine uniform and long-lasting therapeutic responses. Several studies have shown that the reactivation of MAPK signaling is a critical event leading to BRAF inhibitor resistance. These studies lead to the evaluation and subsequent FDA approval of frontline BRAF (dabrafenib) plus MEK (trametinib) inhibitors to delay drug resistance.

Though this approach has meaningful clinical benefit, there are still a number of patients who do not respond to therapy or who, through unknown mechanisms, succumb to refractory disease. In an effort to identify drivers of MAPK inhibitor resistance, several studies have relied on traditional genomics methods. While gene-based approaches have guided precision medicine, they do not address the dynamics of the global signaling changes that occur following acquired resistance.

The dissertation herein will describe our efforts to fill these gaps of knowledge and will expand upon the evolution and development of our understanding of intrinsic and acquired MAPK pathway inhibitor resistance. This work will elaborate on our early understanding of single agent BRAF inhibitor resistance, the use of genomic and proteomic approaches to further elucidate these mechanisms, and evidence based approaches to delay and overcome single agent BRAF inhibitor resistance. This work will describe global phosphoproteomic and bioinformatics methodologies to elucidate the underlying processes of both single (BRAF) and dual agent (BRAF plus MEK) inhibitor resistance as well as strategies to constrain dual agent BRAF plus MEK inhibitor resistance.

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