DOI

10.17077/etd.n7p7-3p5r

Document Type

Dissertation

Date of Degree

Fall 2018

Access Restrictions

Access restricted until 01/31/2021

Degree Name

PhD (Doctor of Philosophy)

Degree In

Free Radical and Radiation Biology

First Advisor

Schultz, Michael K.

First Committee Member

Spitz, Douglas R.

Second Committee Member

Simons-Burnett, Andrean

Third Committee Member

Yang, Ling

Abstract

Melanoma incidence in the United States has grown continuously at a rate of 1.5% each year for the last decade. Disease detected early can be cured by surgery, but metastatic disease is lethal. Recent discoveries have led to promising-targeted MAPK-pathway inhibitors (MAPKih) and immunotherapies. However, low response rates and acquired drug resistance remain as significant challenges to improved outcomes. The mechanisms that drive resistance to MAPKih are elusive. On the other hand, our data suggests that drug-induced alterations in oxidative metabolism and cellular antioxidant systems (e.g., glutathione; GSH and superoxide dismutase; SOD) in melanoma cells play prominent roles in acquisition of resistance to melanoma drugs. Our studies further indicate a correlative relationship between changes in cellular/mitochondrial reactive oxygen species (superoxide, hydrogen peroxide) levels and adaptation of melanoma cells to MAPK pathway inhibition (MAPKi). Interestingly, our findings suggest that drug-induced alterations in the oxidized and reduced GSH balance facilitate acquisition of drug resistance by activating restorative pathways (e.g., the unfolded protein response; UPR and autophagy). Our data further show that inhibiting GSH synthesis using FDA-approved drug buthionine sulfoximine (BSO) in the presence of MAPKih prevents the acquisition of resistance to MAPKih in vitro. Further, simultaneously attenuating ER-stress responses using sodium 4-phenylbutyrate (PBA) and inhibiting autophagy using hydroxychloroquine (HCQ) in combination with MAPKih prevented adaptation to MAPKi in vitro and significantly improved tumor response and overall survival of mice bearing metastatic melanoma xenograft tumors (BRAFi-resistant and sensitive) in vivo. This thesis research focuses on exploring the role of MAPKi-mediated metabolic reprogramming and changes in the oxidative state in melanoma cells and tumors with the acquisition of resistance to MAPKih in metastatic melanoma.

Pages

xii, 116 pages

Bibliography

Includes bibliographical references.

Comments

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Copyright

Copyright © 2018 Somya Kapoor

Available for download on Sunday, January 31, 2021

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