Transcriptional cyclin-dependent kinases as therapeutic targets in bone metastasizing cancers

Cyclin-dependent kinases (CDKs) are established and emerging drug targets in cancer. Clinical success of CDK4/6 inhibitors in HR+/HER2- breast cancer has validated the CDK family therapeutically and stimulated development of both next-generation cell-cycle CDK inhibitors and inhibitors targeting transcriptional CDKs (CDK7-9, CDK11–13 and CDK19). Experience across these programs has shown that the therapeutic value of a CDK inhibitor is determined not only by kinase selectivity, but also by tumor dependency, compensatory pathways, normal-tissue biology, pharmacokinetic exposure and dosing schedule. Transcriptional CDKs are particularly attractive in cancers that depend on highly active oncogenic transcriptional programs, potentially creating a therapeutic window despite their essential roles in normal cells. In this review, we summarize CDKs as cancer drug targets with emphasis on transcriptional CDKs and metastatic disease. We specifically explore the potential of CDK9 inhibition in bone metastases, including effects on both tumor cell survival and RANKL-NF-κB -driven osteoclastogenic bone microenvironment, and discuss how CDK12 and CDK13 may provide complementary or context-dependent therapeutic opportunities.