Hormone-positive breast cancer (HR+) accounts for roughly 70% of all breast cancer diagnoses. Despite the success of CDK4/6 inhibitors as a chemotherapy-free standard of care for metastatic disease, resistance eventually emerges in nearly every patient — and the mechanisms remain incompletely understood.
Our lab investigates therapeutically relevant molecular pathways that drive this resistance. Combining small-molecule kinase inhibitor screens with functional genomics and proximity-labeling proteomics, we uncovered an unexpected interplay between the Hippo pathway and the transcriptional kinase CDK7 — one that may reverse resistance to CDK4/6 inhibition in HR+ breast cancer.
We are clinicians and scientists. Every project is shaped by the questions we cannot yet answer in clinic.
A small-molecule kinase screen combined with functional genomics revealed a previously unknown link between CDK7 and the Hippo pathway. We are dissecting the mechanism using BRET, structural biology, and engineered CDK6 mutants to understand how CDK7 inhibition reverses resistance in HR+ breast cancer.
Presented at AACR 2023 — poster available here →
We discovered a CDK6 mutation (D224Y) that confers resistance without altering inhibitor binding — pointing to undiscovered downstream mechanisms. Using APEX2 proximity labeling and mass spectrometry, we are systematically mapping CDK6's binding partners in wild-type and mutant states.
Chung et al. identified the 14-3-3 protein YWHAB as a mediator of CDK4/6 inhibitor resistance — manuscript under revision.
ADCs have reshaped chemotherapy in HER2-positive and HER2-low breast cancer — but the cellular machinery that governs their internalization is poorly characterized. We are applying proximity labeling to discover the factors and mediators that modulate ADC endocytosis, with the goal of predicting and overcoming resistance before it becomes clinical.
