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.
Dissertation
The role of cellular redox imbalance, ER-stress, and autophagy in adaptation of metastatic melanoma to MAPK pathway inhibition
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Autumn 2018
DOI: 10.17077/etd.n7p7-3p5r
Abstract
Details
- Title: Subtitle
- The role of cellular redox imbalance, ER-stress, and autophagy in adaptation of metastatic melanoma to MAPK pathway inhibition
- Creators
- Somya Kapoor - University of Iowa
- Contributors
- Michael K. Schultz (Advisor)Douglas R. Spitz (Committee Member)Andrean Simons-Burnett (Committee Member)Ling Yang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Free Radical and Radiation Biology
- Date degree season
- Autumn 2018
- DOI
- 10.17077/etd.n7p7-3p5r
- Publisher
- University of Iowa
- Number of pages
- xii, 116 pages
- Copyright
- Copyright © 2018 Somya Kapoor
- Comment
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- Language
- English
- Date submitted
- 03/01/2019
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references.
- Public Abstract (ETD)
Melanoma incidence has increased continuously over the last 10 years, and increases in incidence are particularly pronounced in younger populations (less than 40 y). If diagnosed early, surgical excision of the tumor and adjuvant therapy is largely curative (99% 5 y survival). However, metastatic melanoma is almost always fatal (5 y survival <23%). This can be attributed to low response rates to current FDA-approved treatment options and almost inevitable development of drug resistance for patients that do respond to these drugs. Research groups have identified several possible mechanisms responsible for the development of drug resistance. Unfortunately, no clinical approach has yet been applied effectively that takes advantage of these putative mechanisms.
This thesis focuses on the changes in melanoma-cell metabolism and oxidative state that occur in response to treatment with a specific class of drugs (MAPK pathway inhibitors (MAPKih)). We explore these changes as they arise with prolonged-continuous MAPKih treatment of melanoma cells and tumors, with the goal of understanding their contribution to the development of resistance. Our observations demonstrate that these changes act by activation of a particular cellular protective process called autophagy. Autophagy allows cells to recycle and re-use damaged organelles and protein debris for self-repair and restoration of homeostasis, thereby enabling survival despite cellular insults (e.g., oxidative stress or endoplasmic reticulum (ER) stress). Our data shows that autophagy plays a significant role in assisting melanoma cells in adaptation to (i.e., become resistant to) MAPKih. This thesis shows that if autophagy is inhibited simultaneously with the mechanism that leads to its activation (i.e., Unfolded Protein Response in the ER), development of resistance (adaptation) can be attenuated in melanoma cells; and the rate of tumor growth can be reduced in melanoma mouse models (up to 20% complete responses observed). It is anticipated that such therapeutic combinations have the potential to be introduced clinically to prevent development of drug resistance and improve outcomes for metastatic melanoma patients.
- Academic Unit
- Free Radical and Radiation Biology Program
- Record Identifier
- 9983777107602771
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