The CDK4/6 Inhibitor Palbociclib Inhibits Estrogen-Positive and Triple Negative Breast Cancer Bone Metastasis In Vivo

SIMPLE SUMMARY: When breast cancer (BC) spreads to the skeleton it is no longer curable; new treatments are needed in this setting. When given daily, the CDK4/6 inhibitor palbociclib significantly impedes tumour growth in murine models of both estrogen receptor positive and triple negative bone metastatic BC. When a treatment break was introduced, mimicking the clinical setting, tumour growth resumed and continued even in the presence of further cycles of palbociclib. In combination treatment with bisphosphonate zoledronic acid, or a CDK7 inhibitor, palbociclib was insufficient in preventing tumour growth. This suggests that tumour cells become insensitive to palbociclib after a treatment break. To explore possible underlying reasons for this, we harvested palbociclib-sensitive and -insensitive tumour cells from bone and found differences in the levels of key proteins that palbociclib affects. We provide the first demonstration that palbociclib is effective at reducing breast tumour growth in bone, if given daily. ABSTRACT: CDK 4/6 inhibitors have demonstrated significant improved survival for patients with estrogen receptor (ER) positive breast cancer (BC). However, the ability of these promising agents to inhibit bone metastasis from either ER+ve or triple negative BC (TNBC) remains to be established. We therefore investigated the effects of the CDK 4/6 inhibitor, palbociclib, using in vivo models of breast cancer bone metastasis. In an ER+ve T47D model of spontaneous breast cancer metastasis from the mammary fat pad to bone, primary tumour growth and the number of hind limb skeletal tumours were significantly lower in palbociclib treated animals compared to vehicle controls. In the TNBC MDA-MB-231 model of metastatic outgrowth in bone (intracardiac route), continuous palbociclib treatment significantly inhibited tumour growth in bone compared to vehicle. When a 7-day break was introduced after 28 days (mimicking the clinical schedule), tumour growth resumed and was not inhibited by a second cycle of palbociclib, either alone or when combined with the bone-targeted agent, zoledronic acid (Zol), or a CDK7 inhibitor. Downstream phosphoprotein analysis of the MAPK pathway identified a number of phosphoproteins, such as p38, that may contribute to drug-insensitive tumour growth. These data encourage further investigation of targeting alternative pathways in CDK 4/6-insensitive tumour growth.