Therapeutically targeting autophagy in non-small cell lung cancer
Autophagy is a conserved catabolic pathway which sequesters intracellular components in lysosomes to recycle macromolecules for cell maintenance. The role of autophagy in tumor cells is dynamic and depends on many factors including tumor types, tumor stages, and activity of several tumor suppressors and oncogenes. In this thesis, I wanted to improve our understanding of the unique relationship of autophagy with tumor suppressor p53 and oncogenic KRAS in cancer cells, particularly in NSCLC. First, I demonstrated that stabilized nuclear wild-type p53 through HDM2 inhibition with MK-8242 or nutlin-3a could induce autophagy in tumor cells through transactivation of several autophagy-related genes (DRAM, FOXO3A, SESN2, and MRCKα) and autophagy core genes (ATG4A and ULK1). In addition, I found that inhibiting of KRAS G12C signaling and suppressing mTORC1 activity by selective KRAS G12C inhibitor, ARS-853, could drive autophagy response in KRAS G12C NSCLC cell lines. Since autophagy could also promote survival under stress induced by several anticancer agents, I designed a combination study using newly reported selective ULK1 inhibitor, ULK-101, with ARS-853 in KRAS mutant NSCLC. Autophagy inhibition with ULK-101 dramatically enhanced the ability of selective KRAS G12C inhibitor to impair the viability of KRAS G12C NSCLC. Together, my study provided evidence that autophagy serves as a survival pathway in tumor cells and that future assessment of small molecule that target autophagy core proteins may be potential cancer therapeutic option in p53 wild-type and KRAS G12C NSCLC.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Yco, Lisette Pangilinan
- Thesis Advisors
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MacKeigan, Jeffrey P.
Doseff, Andrea
- Committee Members
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Gallo, Kathleen
Andrechek, Eran
- Date
- 2019
- Subjects
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Cytology
Molecular biology
Physiology
- Program of Study
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Physiology - Master of Science
- Degree Level
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Masters
- Language
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English
- Pages
- 136 pages
- ISBN
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9781392088128
1392088127