Inhibition of the Calcium Calmodulin Kinase Kinase-2/phosphodiesterase-1 signaling pathway as a therapeutic approach in metastatic breast cancer.

Breast cancer has surpassed lung cancer as the leading cause of cancer incidence, with an estimated 2.3 million new cases in 2020, representing approximately 11.7% of all cancer cases worldwide. It remains the most common cause of cancer-associated death among women. Independent of subtype, ~90% of all breast cancer related deaths can be attributed to metastasis, a generally incurable state of disease for which there are few effective therapies. This contextually puts our discovery of a new calcium-dependent signaling pathway, which is elaborated in both cancer cells and within tumor associated macrophages (TAMs), that regulates processes of pathological importance in tumors/metastatic lesions in animal models of advanced breast cancer. Notable was the finding that genetic or pharmacological inhibition of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) activity reduces cancer cell migration/invasion in vitroand metastasis from tumors in vivo. This was determined to be a result of decreased expression of phosphodiesterase-1A (PDE1A), decreased cGMP hydrolysis, and increased activation of protein kinase G (PKG). This ultimately leads to increased phosphorylation of the vasodilator-stimulated phosphoprotein (VASP), interfering with its‘ ability to participate in the actin remodeling activities needed for metastatic progression. Genetic or pharmacological manipulation of PDE1 activity recapitulates these findings. Likely modulating a similar signaling pathway, both CaMKK2 and PDE1 inhibitors also facilitate a favorable polarization of TAMs which in turn increases the number of functionally active cytotoxic T-cells in tumors. Thus, CaMKK2/PDE1 inhibitors represent a novel new class of cancer therapeutics that function by both altering fundamental aspects of cancer cell biology and increasing tumor immunity.