Targeting Autophagy to Improve Efficacy of Cdk4/6 Inhibition In Breast Cancer

<p>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 <em>in vitro</em> 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.</p> <p>Thus, we hypothesize that <strong>in the presence of an intact G1/S checkpoint, autophagy protects ER positive breast cancer cells from palbociclib induced senescence</strong>. Further, based on our preliminary results, we hypothesize that cancer stem cells and EMT mediates acquired resistance to palbociclib.</p> <p>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 <em>in vitro,</em> and diminishes growth of cell line and patient-derived xenograft tumors <em>in vivo</em>. 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2017

Authors dc:creator

• Vijayaraghavan, Smruthi
• <p>0000-0002-8131-0988</p>

Contributors dc:contributor

• Khandan Keyomarsi, Ph.D.
• Jeffrey N. Myers, MD.
• Robert C. Bast Jr., MD.

• Breast cancer
• cell cycle
• CDK4/6 inhibitor
• autophagy
• senescence
• biomaker
• drug resistance
• Cancer Biology
• Life Sciences
• Medicine and Health Sciences
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/772

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1814