Anna Zimmerman
Research Mentor(s): Alnawaz Rehemtulla
Mentor Department: Radiation Oncology
Authors: Anna Zimmerman, Alnawaz Rehemtulla, Armaan Gilani, Sahezeel Awadia
Session: Session 2 (10:00am – 10:50am)
Presentation Type: Poster 61
Abstract
Breast cancer is the most diagnosed cancer globally, with most cases being of the luminal subtype. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with aromatase inhibitors or fulvestrant are the standard treatment for metastatic endocrine-sensitive luminal breast cancer. These therapies block the G1 to S cell cycle transition and significantly extend progression-free survival. However, resistance to CDK4/6i is common, and treatment options post-recurrence are limited due to poor understanding of the mechanisms underlying resistance. Our lab discovered that CDK4/6i resistance arises from an alternate pathway for G1 to S transition, bypassing the canonical CDK4/6-Rb-E2F axis. This pathway involves the Fas-associated protein with death domain (FADD), which inhibits APC/C-Cdh1 E3-ligase activity when phosphorylated at Ser194 by CK1a. We observed a marked increase in phosphorylated FADD (pFADD) in CDK4/6i-resistant breast cancer, using cell models, mouse studies, and patient tumor biopsies. Targeting FADD phosphorylation with a novel CK1a inhibitor restores CDK4/6i sensitivity. My UROP project explores PEA15 as a mediator of FADD phosphorylation in CDK4/6i-resistant breast cancer. Our first aim was to test whether PEA15 forms a complex with CK1a and FADD to promote FADD phosphorylation at Ser194, using siRNA/shRNA knockdown in resistant MCF7 and T47D cells, followed by western blotting and immunocytochemistry. Our next aim was to investigate if phosphorylation of PEA15 at Ser116 by AKT, linked to FGFR, PIK3CA, and AKT1 mutations, modulates its role in mediating FADD phosphorylation. Mutants of PEA15 (Ser116Ala and Ser116Asp) will be tested to evaluate their impact. This research aims to elucidate the role of FGFR, PIK3CA, and AKT in CDK4/6i resistance.
