Breast cancer is the most frequent women cancer worldwide. Estrogen receptor (ER)-positive breast cancer accounts for the majority of breast cancer. One of the first line therapies for ER-positive breast cancer is selective ER modulator, tamoxifen. Palbociclib is a FDA-approved CDK4/6 inhibitor for treatment of metastatic breast cancer after hormone therapy resistance.

Although palbociclib shows significant therapeutic benefit, drug resistance to CDK4/6 inhibitor remains a clinical challenge, with little is known about the molecular mechanism. Therefore, we aim to unlock the underlying mechanism in palbociclib resistance.

We have established the sequential drug resistant cell lines from tamoxifen resistance to palbociclib resistance. Using RNA sequencing, we identified activated estrogen and HER2 pathways as potential targets. We also discovered enriched kinases (CDK1, 2 and 4) and transcription factor, SUZ12, which may be involved in palbociclib resistance. Functional analysis shows that increased proliferation, migration, angiogenesis and ECM disassembly are observed in palbociclib-resistant cells.

In this study, we will uncover the molecular mechanism and functional outcomes of palbociclib resistance that provide potential therapeutic strategies.