Author ORCID Identifier

0000-0002-8131-0988

Date of Graduation

5-2017

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Khandan Keyomarsi, Ph.D.

Committee Member

Jeffrey N. Myers, MD.

Committee Member

Robert C. Bast Jr., MD.

Committee Member

Sendurai Mani, Ph.D.

Committee Member

Raghu Kalluri, MD, Ph.D.

Committee Member

Stephanie S. Watowich, Ph.D.

Abstract

Deregulation of the cell cycle machinery is a hallmark of cancer, leading to aberrant proliferation and tumorigenesis. The crucial role of the CDK4/6-Cyclin D pathway has led to the development and FDA approval (palbociclib, ribociclib) of CDK4/6 inhibitors for the treatment of advanced estrogen receptor positive breast cancer. However, three major clinical challenges remain: i) adverse events leading to discontinuation of therapy and ii) lack of reliable biomarkers to identify responsive patients and iii) acquired resistance to CDK4/6 inhibitors. Previous in vitro studies have shown that palbociclib mediated CDK4/6 inhibition induces G1 arrest and senescence in ER+ breast cancer cells, and a recent study in fibroblasts implicated a role for palbociclib in inducing autophagy, a catabolic process that facilitates survival of the cells under stress.

Thus, we hypothesize that in the presence of an intact G1/S checkpoint, autophagy protects ER positive breast cancer cells from palbociclib induced senescence. Further, based on our preliminary results, we hypothesize that cancer stem cells and EMT mediates acquired resistance to palbociclib.

Results from this study show that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumors in vivo. Furthermore, intact G1/S transition is necessary and predictive of preclinical sensitivity to this drug combination, and Rb positive and low-molecular-weight isoform of cyclin E negative status are reliable prognostic biomarkers in advanced estrogen receptor positive breast cancer patients. Inhibition of CDK4/6 and autophagy was also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumors. Lastly, combined targeting with STAT-3 and PARP inhibitors can effectively target acquired resistant to palbociclib. Collectively, results from this study can help improve the efficacy, selectivity and treat acquired resistance to CDK4/6 inhibition in breast and other solid tumors.

Keywords

Breast cancer, cell cycle, CDK4/6 inhibitor, autophagy, senescence, biomaker, drug resistance

Available for download on Saturday, May 05, 2018

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