File(s) under embargo

Reason: The file contains unpulished data

1

year(s)

6

month(s)

26

day(s)

until file(s) become available

PLK1 AS A PROMISING TARGET IN THE CANCER TREATMENT

thesis
posted on 07.12.2020, 20:58 by Fengyi Mao

Polo-like kinase 1 (PLK1) is a critical cell cycle regulator and overexpressed in multiple cancer types. As previously reported, PLK1 is tightly related to patient survival and cancer progression. Prostate cancer (PCa) is the most frequently diagnosed cancer in men and the second leading cause of cancer-associated death in the US. Once PCa patients develop resistance toward initial androgen deprivation therapy (ADT), the castration-resistant prostate cancer (CRPC) will occur and become lethal. Thus, a novel therapeutic strategy to treat CRPC patients is urgently required. Herein, we have identified a novel combination therapy that PLK1 inhibitor GSK461364A and BRD4 inhibitor JQ1 cooperate to treat CRPC both in vitro and in vivo. GSK461364A and JQ1 act synergistically to inhibit cell proliferation and induce cell apoptosis through regulating c-MYC and AR signaling and dramatically impact cell metabolism as well.

Furthermore, the progression of malignant melanoma, the most aggressive and deadly skin cancers, also firmly correlates with the PLK1 expression level in patients. In this study, we have utilized the mouse melanoma model BrafCA/+ / Ptenloxp/loxp to investigate the role of Plk1 in melanoma progression and metastasis. Elevated expression of Plk1 significantly shortened the survival period, promoted proliferation, induced metastasis, and impacted metabolism in mouse melanoma models. Intriguingly, PLK1 also contributes to the drug resistance toward PLX-4032, which is the FDA-approved drug to treat metastatic melanoma patients harboring BRAF V600E mutation. Therefore, the efficacy of combining PLX-4032 and PLK1 inhibitor BI6727 has been tested in human melanoma cell lines and the xenograft model, showing a strong synergy between the two drugs. To conclude, we have demonstrated that PLK1 functions as an oncogene in cancer development, and targeting PLK1 would be a promising therapeutic strategy in clinic.


Funding

R01 CA157429

R01 CA192894

R01 CA196835

R01 CA196634

History

Degree Type

Doctor of Philosophy

Department

Animal Sciences

Campus location

West Lafayette

Advisor/Supervisor/Committee Chair

Dr. Shihuan Kuang

Advisor/Supervisor/Committee co-chair

Dr. Xiaoqi Liu

Additional Committee Member 2

Dr. Ourania M. Andrisani

Additional Committee Member 3

Dr. Ryan Cabot

Licence

Exports

Licence

Exports