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Targeting Tyrosine Kinase Drug Resistance Mechanisms and Metastatic Pathways in Brain Tumors

Aljohani, Hashim M
http://orcid.org/0000-0001-5333-6956
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846160285645

Abstract Details

2020, PhD, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
The goal of this dissertation is to improve our understanding of two important processes in carcinogenesis: First, the resistance mechanisms to tyrosine kinase inhibitors in glioblastoma (GBM). Second, the mechanisms involved in the metastatic spread of non-small cell lung cancer (NSCLC) to the brain. Malignant gliomas have a poor prognosis, as recurrence remains nearly inevitable despite aggressive treatment with a median survival time of 12-15 months. Primary GBM usually displays amplification or mutation of at least one receptor tyrosine kinase, most often the epidermal growth factor receptor (EGFR). Targeting EGFR for inhibition often provides an initial tumor response in patients, but recurrence is a main limitation of these therapies because secondary mutations emerge that lead to drug resistance. In this work, we identified a receptor tyrosine kinase, proto-oncogene ROS1 fusion, that drives the resistance to therapy and leads to tumorigenesis in GBM. In parallel, the aggressive metastatic phenotype is one of the hallmarks of recurrent tumors, and its estimated that 90% of all cancer deaths arise from the metastatic spread of primary tumors. Of all the processes involved in carcinogenesis, local invasion and the formation of metastases are clinically the most relevant, but the least well understood at the molecular level. This work also provides evidence for the use of circulating tumor cells as a biomarker for the metastatic spread of cancer, specifically in lung cancer. To uncover the molecular changes that govern the transition from a primary lung tumor to a secondary metastasis and specifically the mechanisms by which circulating tumor cells (CTCs) survive in circulation, we carried out whole genome sequencing of normal lung tissue, primary tumors, and the corresponding brain metastases from five patients with progressive metastatic NSCLC. We also isolated CTCs from patients with metastatic cancer and subjected them to whole genome amplification and Sanger sequencing of genes of interest. Whereas the primary tumors showed mutations in genes associated with cell adhesion and motility, brain metastases acquired mutations in adaptive, cytoprotective genes involved in the response to cellular stress, namely Kelch ECH associating protein (Keap1), nuclear factor erythroid 2-related factor 2 (NRF2), and P300, which are the key players of the Keap1-NRF2-ARE survival pathway. NRF2 is a transcriptional factor that translocates into the nucleus upon stress, binds to the antioxidant response elements (ARE), and drives the expression of antioxidant genes. The identified mutations affect regulatory domains in all three proteins, suggesting a functional role in providing a survival advantage to CTCs in the peripheral blood that allows their dissemination to distant organs. We identified a combination therapy strategy tailored to specific genetic alterations prevalent in primary GBM and identified novel targets for preventing cancer metastasis. We are the first to report ROS1-mediated gefitinib resistance in GBM cells and shown that these cells are remarkably sensitive to ROS1 inhibition in combination with gefitinib. Additionally, investigating mutations in the key players of the NRF2 antioxidant pathway that can be targeted therapeutically with NRF2 inhibitors is a promising approach to prevent cancer metastasis.
Peter Stambrook, Ph.D. (Committee Chair)
El Mustapha Bahassi, Ph.D. (Committee Member)
Pankaj Desai, Ph.D. (Committee Member)
Rhett Kovall, Ph.D. (Committee Member)
William Miller, Ph.D. (Committee Member)
160 p.
Biochemistry
Brain tumors; Glioblastoma; Non-small lung cancer; Tyrosine kinase inhibitors; Brain Metastasis; Circulating Tumor Cells

Recommended Citations

Citations

  • Aljohani, H. M. (2020). Targeting Tyrosine Kinase Drug Resistance Mechanisms and Metastatic Pathways in Brain Tumors [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846160285645

    APA Style (7th edition)

  • Aljohani, Hashim. Targeting Tyrosine Kinase Drug Resistance Mechanisms and Metastatic Pathways in Brain Tumors. 2020. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846160285645.

    MLA Style (8th edition)

  • Aljohani, Hashim. "Targeting Tyrosine Kinase Drug Resistance Mechanisms and Metastatic Pathways in Brain Tumors." Doctoral dissertation, University of Cincinnati, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1595846160285645

    Chicago Manual of Style (17th edition)

ucin1595846160285645
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This open access ETD is published by University of Cincinnati and OhioLINK.