CDK4/6 and DNA repair role in cancer

Synthetic lethality and novel targeted therapies

We found that cyclin-dependent kinases CDK4/6 drives breast cancer stem cell (CSC) self -renewal activities and showed that their pharmacological inhibition efficiently eliminates CSCs. We further uncovered new use/repurposing for FDA approved drugs (palbociclib, celecoxib) in the treatment of metastatic cancer by targeting and eliminating self-renewing CSCs21 and by re-sensitizing (dasatinib) resistant cancer cells to chemotherapy. These studies also led to the development of a new dual targeting kinase inhibitor lead compound (USPTO patent filing EFS ID 40804961; Application Number 17066824; Title: Single molecules having mixed CDK4/6, PLK1 targeting properties. Filling date: Oct 9, 2020).

Although CDK4 and CDK6 play fundamental roles in cancer, the specific pathways and downstream targets by which they exert their effects remain elusive.

By combining in vivo CRISPR-based CDK4/6 gene editing with pharmacological inhibition approaches in orthotopic transplantation and patient-derived xenograft preclinical models we uncovered distinct and novel functions for CDK4 and CDK6 in regulating tumorigenesis and metastasis. Transcriptomic profiling of CDK4/6 CRISPR knockouts revealed that while CDK4 regulated pro-metastatic inflammatory cytokine signaling, CDK6 mainly controlled DNA replication and repair processes. Inhibition of CDK6 but not CDK4 resulted in defective DNA repair and increased DNA damage. We found multiple CDK6 DNA repair genes to not only associate with cancer subtypes, grades, and poor clinical outcomes, but also to facilitate primary tumor growth and metastasis in vivo. CRISPR-based genomic deletion of CDK6 efficiently blocked tumorigenesis in pre-established cell- and patient-derived xenograft preclinical models of metastatic breast cancers, providing a potential novel targeted therapy for these deadly tumors. These recent studies lay the foundation for one of our main research project, aiming at elucidating CDK6/DNA repair functions and contributions towards TNBC tumorigenesis. We are currently defining mechanisms of CDK4/6i drug resistance, identifying and further exploiting synthetic lethal drug targets for CDK4/6i to improve patient stratification, clinical benefits and outcome for triple negative breast cancer patients.