The Combination of the CDK4/6 Inhibitor, Palbociclib, With the Vitamin D Analog, Inecalcitol, Has Potent and Anticancer Effects in Hormone-Sensitive Breast Cancer, But Has a More Limited Effect in Triple-Negative Breast Cancer.

Active vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)D], and its synthetically derived analogs possess potent anticancer properties. In breast cancer (BC) cells, 1,25(OH)D blocks cell proliferation and induces apoptosis through different cell-type specific mechanisms. In this study, we evaluated if the combination of the potent vitamin D analog, inecalcitol, with a selective CDK4/6 inhibitor, palbociclib, enhanced the antiproliferative effects of both single compounds in hormone-sensitive (ER) BC, for which palbociclib treatment is already approved, but also in triple-negative BC (TNBC).

The role of vitamin D in breast cancer risk and progression.

The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is primarily known as a key regulator of calcium and phosphate homeostasis. It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH)2D3.

Vdr expression in osteoclast precursors is not critical in bone homeostasis.

The long-recognized role of the vitamin D endocrine system is to maintain stable serum calcium concentrations, which are ensured by a complex interplay between parathyroid gland, kidney, intestine, and bone. However, although VDR is expressed in osteoclastogenic cells, the contribution of VDR-mediated signaling to osteoclast differentiation and activity remains undefined. We therefore deleted Vdr expression efficiently and specifically in myeloid cells by use of M lysozyme-driven Cre expression, which targets granulocytes, monocytes, macrophages and osteoclasts (Vdr mice).

WY 1048, a 17-methyl 19-nor D-ring analog of vitamin D, in combination with risedronate restores bone mass in a mouse model of postmenopausal osteoporosis.

Bisphosphonates like risedronate inhibit osteoclast-mediated bone resorption and are therefore used in the prevention and treatment of osteoporosis. Also vitamin D and calcium supplementation is commonly used in the prevention or treatment of osteoporosis. Combined therapy of risedronate with 1,25(OH)D, the active metabolite of vitamin D, may be advantageous over the use of either monotherapy, but bears a risk of causing hypercalcemia thereby decreasing the therapeutic window for osteoporosis treatment.