Dissertation
Unveiling resistance mechanisms and improving therapeutic outcomes in mutant BRAFV600E cancers
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2024
DOI:
https://doi.org/10.17918/00010582
Abstract
8% of all human cancers are driven by an activating mutation (V600E/K) in the BRAF protein (Mendiratta et al., 2022), a serine-threonine kinase central to the Mitogen-Activated Protein Kinase (MAPK) pathway. Small molecule inhibitors targeting malignant cells carrying a BRAFV600E mutation (BRAFi) have proven to have clinical efficacy. However, patient response varies across different cancer types, and resistance, whether innate or acquired, is a major challenge. Mutant BRAFV600E is predominantly expressed in papillary thyroid carcinomas (PTC) (~60%) and melanomas (~50%) (Owsley et al., 2021). Melanoma patients typically exhibit a significant initial reduction in tumor burden in response to BRAFi treatment. However, resistance is inevitably acquired 6-9 months into treatment (Flaherty et al., 2012). In contrast, patients with PTC respond poorly to BRAFi, indicating an innate resistance. Programmed cell death mechanisms play a role in BRAFi efficacy, and resistance to apoptosis drives relapse in many mutant-BRAF cancers. Therefore, understanding the role of cell death machinery in resistance and relapse could help guide more durable treatment strategies against mutant BRAF cancers. In this study, we investigate the role of programmed cell death mechanisms in providing response to BRAFi in PTC and melanoma models. We first characterize a role for the Bcl-2 family member Mcl-1 in contributing to a failed apoptotic phenotype, which drives innate resistance in BRAFV600E PTC. Additionally, we explore the role of immunogenic cell death in providing anti-tumor immune responses capable of clearing drug-tolerant persisters (DTPs) in a syngeneic mouse model of melanoma brain metastases (MBM). These studies aim to elucidate the mechanisms underlying innate resistance in PTC models and work to combat acquired resistance and minimal residual disease (MRD) in melanoma models. By doing so, we enhance our understanding of therapeutic response to BRAFi, addressing both innate and acquired resistance phenotypes across different mutant BRAFV600E cancers with a goal of contributing to improved treatment outcomes.
Metrics
11 File views/ downloads
21 Record Views
Details
- Title
- Unveiling resistance mechanisms and improving therapeutic outcomes in mutant BRAFV600E cancers
- Creators
- Maria Cavallo
- Contributors
- Edward J. Hartsough (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 161 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991021902014104721