Date of Award

2014-01-01

Degree Name

Master of Science

Department

Biological Sciences

Advisor(s)

Robert A. Kirken

Abstract

Chronic Myeloid Leukemia (CML) has served as a model for how cancer can be selectively targeted with advanced forms of chemotherapies known as kinase inhibitors. Such new therapies have significantly altered the field of oncology and have led to monumental increases in both survival rates and quality of life for cancer patients. However, approximately one-third of CML patients will go on to develop drug resistance against major kinase inhibitors. Along with this, other cancers are showing increased incidences of drug resistance. Understanding how these cancers, such as CML, overcome drug sensitivity is of major importance within the clinic. To predict potential cell signaling pathways utilized in drug resistant CML, we generated a highly drug resistant T315I BCR-Abl mutant CML cell line from the already established KCL-22 cell line. With our established cell line we analyzed the activity of several cell signaling pathways that serve roles in controlling cellular proliferation, cellular differentiation, and cell death. In contrast to the wild type KCL-22 cell line, we were able to identify MEK1/2 and mTOR dependency within the drug resistant mutant. These findings allowed us conclude that FDA approved kinase inhibitors Trametinib (a MEK1/2 inhibitor) and Temsirolimus (an mTOR inhibitor) may hold therapeutic value in selectively targeting T315I BCR-Abl CML tumor cells. Lastly, using a series of bioinformatics tools such as PROVEAN and SIFT, we analyzed the genomic landscape of both the wild type and artificially established drug resistant CML mutant in order to identify genetic alterations that may be associated with drug insensitivity. From this genomic analysis we were able to identify several novel mutations within the drug resistant mutant that occur within key regulatory sites of various cell signaling molecules. In conclusion, CML drug insensitivity can be overcome by targeting downstream targets of BCR-Abl such as MEK1/2 or mTOR, and various mutations besides the T315I BCR-Abl variant may contribute to drug insensitivity.

Language

en

Provenance

Received from ProQuest

File Size

128 pages

File Format

application/pdf

Rights Holder

Derrick Matthew Oaxaca

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