Research ArticleCancer

Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion

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Science Translational Medicine  26 Apr 2017:
Vol. 9, Issue 387, eaal3986
DOI: 10.1126/scitranslmed.aal3986

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Rock-a-bye stem cells

Traditional chemotherapy can be quite effective against cancer, but its efficacy is often reduced by dose-limiting side effects. Because this type of therapy kills rapidly dividing cells, one of the most common toxicities is hematologic, resulting from chemotherapy drugs killing normal hematopoietic cells in the bone marrow. To protect the healthy hematopoietic stem cells, He et al. devised a method of combining chemotherapy with an inhibitor of cyclin-dependent kinases 4 and 6, which transiently suppresses the cell cycle in normal cells but not in malignant ones. The authors tested their drug with chemotherapy in mice to show protection from myelotoxicity, and they performed a human trial demonstrating its safety in healthy volunteers.

Abstract

Conventional cytotoxic chemotherapy is highly effective in certain cancers but causes dose-limiting damage to normal proliferating cells, especially hematopoietic stem and progenitor cells (HSPCs). Serial exposure to cytotoxics causes a long-term hematopoietic compromise (“exhaustion”), which limits the use of chemotherapy and success of cancer therapy. We show that the coadministration of G1T28 (trilaciclib), which is a small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), contemporaneously with cytotoxic chemotherapy protects murine hematopoietic stem cells (HSCs) from chemotherapy-induced exhaustion in a serial 5-fluorouracil treatment model. Consistent with a cell-intrinsic effect, we show directly preserved HSC function resulting in a more rapid recovery of peripheral blood counts, enhanced serial transplantation capacity, and reduced myeloid skewing. When administered to healthy human volunteers, G1T28 demonstrated excellent in vivo pharmacology and transiently inhibited bone marrow (BM) HSPC proliferation. These findings suggest that the combination of CDK4/6 inhibitors with cytotoxic chemotherapy should provide a means to attenuate therapy-induced BM exhaustion in patients with cancer.

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