Author ORCID Identifier


Date of Graduation


Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Steven H. Lin, M.D., Ph.D.

Committee Member

Junjie Chen, Ph.D.

Committee Member

Lei Li, Ph.D.

Committee Member

Faye M. Johnson, M.D., Ph.D.

Committee Member

Yang Xia, M.D., Ph.D.


Lung cancer is the leading cause of cancer-related death. While radiation therapy is one of the standard treatments for lung cancer, the disease outcome after radiotherapy is still far from satisfactory despite ongoing advances in radiation techniques. Enhancing the radiosensitivity of lung cancer has the potential to improve the disease outcome of radiation treatments. Using a novel high throughput radiation sensitizing screen, previous work in the lab has identified several potent radiation sensitizers. The focus of my dissertation is on two of the identified pathways, HSP90 and MEK, using the potent and clinically relevant inhibitors ganetespib and trametinib. Using both in vitro experiments in multiple non-small cell lung cancer (NSCLC) cell lines and in vivo experiments in animal models, I tested the ability of these inhibitors to radiosensitize lung tumors in the clinically relevant context of chemoradiation. I have found that ganetespib sensitized lung cancer cells to radiation through attenuating DNA damage repair through attenuating DNA damage repair and accentuating G2-M cell cycle arrest. However, when combined with chemoradiation in vivo, ganetespib has variable effects on different cells. For radiation sensitization through MEK inhibition, I found that trametinib selectively sensitized KRAS-LKB1 co-mutant NSCLC, but not KRAS-TP53 mutant cells, through radiation-induced senescence. In the LKB1 wild type background, trametinib and radiation activated AMPK-autophagy pathway to rescue cells from senescence, therefore conferring resistance to the radiosensitization. In summary, my studies which focused on how these two specific targeted pathways caused radiation sensitization emphasized the need to better understand the molecular and signaling complexities in determining radiation sensitization effects especially when multiple modalities are combined. Preclinical studies in the context of clinically relevant treatment settings are warranted for optimal clinical translation and personalized cancer therapy.


lung cancer, radiotherapy, radio sensitization, KRAS, LKB1



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