Jacinda Liu
Pronouns: she/her
Research Mentor(s): Yuanyuan Qiao
Research Mentor School/College/Department: Pathology – Ctr for Translational Pathology / Medicine
Program:
Authors: Jacinda Liu, Ahmet Korkaya, Sarah Yee, Arul Chinnaiyan, Yuanyuan Qiao
Session: Session 7: 4:40 pm – 5:30 pm
Poster: 28
Abstract
Autophagy is a vital homeostatic cellular recycling process which can be co-opted by various cancers. Inhibition of the lipid kinase PIKfyve demonstrates an interruption of cellular autophagy and consequently limits the progression of tumors such as prostate cancer. Multi-tyrosine kinase inhibitors of PIKfyve, like ESK981, have been highlighted as promising treatment methods for several aggressive cancer types and are currently in clinical trials. Additionally, degradation of PIKfyve with highly specific proteolysis-targeting chimeras may be an even more profound method. Still, there remains a necessity to investigate eventual tumor resistance to PIKfyve targeting and avenues of improved therapeutic efficacy. One potential avenue is combining therapies. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and transcriptional regulator that can drive the expression of several tumor promoting genes and has long been approached as a target in many cancers. BRD4 inhibitors terminate the transcription and eventual translation of these tumor promoting genes, hindering tumor progression. Interestingly, BRD4 has been shown to repress cellular autophagy, so targeting BRD4 leads to increased autophagy in cancer cells. Given the link between increased autophagy and highly aggressive cancers, we hypothesize the targeting of PIKfyve may potentiate cancer cells to BRD4 inhibition. Conversely, BRD4 inhibition may potentiate cancer cells to PIKfyve targeting through reduced expression of alternative survival pathways. Thus, we are investigating the complementary and synergistic effect of multiple PIKfyve inhibitors and degraders with BRD4 inhibitors and degraders on prostate and pancreatic cancer cell lines. Through cell proliferation assay, qPCR, and western blotting experiments we aim to understand the therapeutic efficacy of dual targeting of PIKfyve and BRD4 in cancer. These results will decide whether to further study this combination therapy through in vivo experiments.
