Identifying Novel Factors Involved in Cancer Therapy Sensitivity and Resistance using Genome-Wide CRISPR Screens
Restricted (Penn State Only)
- Author:
- Pale, Lindsey
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 01, 2024
- Committee Members:
- James Broach, Major Field Member
Zhonghua Gao, Major Field Member
George Moldovan, Chair & Dissertation Advisor
Lisa Shantz, Program Head/Chair
Lisa Shantz, Outside Unit & Field Member - Keywords:
- CRISPR
DNA Repair
DNA Damage
Cancer
BRCA
Cisplatin
PARP Inhibitor
PRIMPOL - Abstract:
- Developing long lasting and robust treatment plans for cancer patients is critical for promoting increased survival and decreasing rates of recurrence. While a lot of groundbreaking research in the last few decades have improved cancer treatment strategies in the clinic, resistance to therapies remains an obstacle in achieving durable responses. Just as cancer is clever and ever adapting, research must be as well. This is particularly important for patients with cancers that are difficult to screen for, such as ovarian cancer, as these patients are typically diagnosed late stage. Genome stability and DNA damage is a major hallmark of cancer and a vulnerability that is currently being exploited by many current chemotherapies and emerging targeted therapies in the clinic. In this dissertation I use genome-wide CRISPR knockout screens to identify genetic determinants of PARP inhibitor resistance and cisplatin sensitivity, both commonly used in the clinic to treat breast and ovarian cancers, among others. Specifically, using a previously published CRISPR knockout screen from the lab, I will reveal a novel mechanism of resistance to PARP inhibitors in BRCA-deficient cells, as well as a potential strategy to overcome this resistance. I will then demonstrate how a CRISPR knockout screen can be executed and employed to identify regulators of cisplatin sensitivity in a BRCA-proficient background. More specifically, I will be investigating a novel mechanism of replicative single-stranded DNA gap processing, an emerging determinant of chemotherapy sensitivity in the field, and the implications this may have on response to cisplatin treatment. My work reveals novel determinants and mechanisms of drug response to relevant cancer therapies in breast and ovarian cancer, as well as new biomarkers and targets that can be used in the clinic to inform personalized treatment strategies and improve patient response.