Julianne Thomas
Pronouns: she/her/hers
Research Mentor(s): Alnawaz Rehemtulla
Co-Presenter:
Research Mentor School/College/Department: Radiation Oncology / Medicine
Presentation Date: April 20
Presentation Type: Poster
Session: Session 1 – 10am – 10:50am
Room: League Ballroom
Authors: Julianne Thomas, Alnawaz Rehemtulla, Sahezeel Awadia
Presenter: 11
Abstract
Cancer is a disease of uncontrolled cell growth due to mutations that lead to continued entry into the cell cycle. Drugs have been developed that target the cell cycle, and have proven to be effective in treating breast cancer patients. Cyclin-dependent kinases 4 and 6 (CDK4/6) are enzymes that enable cancer cells to transition between the G1 and S phase of the cell cycle and make daughter cells. In order for this function to be inhibited, CDK4/6 inhibitors have been developed to treat patients with cancer, including breast cancer, to prevent the continuation of cells through the cell cycle. While these treatments have been effective, many women with breast cancer develope resistance to CDK4/6 inhibitors, causing the cancer cells to proceed to the S phase and thus divide. The mechanism by which cancer cells become resistant to CDK4/6 inhibition remains unclear, hence the management of women who stop responding to these agents has been a challenge. To better understand how resistance to these drugs developes, we have used fluorescent reporters called PIP-FUCCI, that allow precise measurement of time it takes to transition from G1 to S in cells grown in a dish. Our hypothesis is that the FADD (Fas Associated Death Domain) protein contributes to the development of resistance to CDK4/6 inhibitors. Previous research has shown that compared to the transition time from G1 to S in the presence of a CDK4/6 inhibitor, the transition time for cancer cells in presence of a CDK4/6 inhibitor in addition to FADD expression reduced the time by one half. In order to truly understand if resistance to CDK4/6 inhibition is caused by expression of the FADD protein, the effect of levels of expression of the FADD protein can be studied. Stable cells called PIP-FUCCI that express FADD constructs will be used to monitor expression of FADD. The amount of FADD expressed depends on the amount of chemical called Doxycycline that is added to the PIP-FUCCI cells. We will evaluate if increased expression of FADD results in changes in the time required for G1 to S transition in sensitive and CDK4/6 resistant cancer cells. This analysis can help determine how resistance to CDK4/6 inhibition can be overcome, and more importantly, this analysis can lead to support for the development of treatments that inhibit FADD function. My project utilizes genetically engineered cells wherein doxycycline treatment leads to FADD expression. This was further explored with the use of three different cancer cell lines: (1) HALO-FADD (Wild Type), (2) HALO-FADD (Ser194-Ala), and (3) HALO-FADD(Ser194-Ala). The effect of FADD expression (wild-type and mutant) was used to evaluate the effect of the Serine-194 site within FADD on cell cycle progression. Our hypothesis is that Serine-194 needs to be phosphorylated for FADD’s function in G1 to S cell cycle progression. If this is true, we could use drugs that prevent FADD-phosphorylation to restore sensitivity to CDK4/6 inhibitors.
Biomedical Sciences, Interdisciplinary
