Abstract IA11: Transient CDK4/6 inhibition protects hematopoietic progenitors from chemotherapy-induced exhaustion

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. I will discuss the use of small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) contemporaneously with DNA damaging stimuli such as cytotoxic chemotherapy to protect HSPC from chemotherapy-induced exhaustion. Specifically, CDK4/6 inhibitors will reduce HSPC proliferation, leading to decreased damage from cytotoxic agents, resulting in preserved HSPC function acutely after bone marrow injury as well as late time points well after hematopoietic recovery. In particular, I will show this approach leads to enhanced long-term HSC function resulting in enhanced serial transplantation and reduced myeloid skewing. I will discuss similarities between chemotherapy-induced HSC dysfunction and HSC aging. Moreover, these finding suggest that the combination of CDK4/6 inhibitors with DNA damaging chemotherapy provides a means to prevent therapy-induced bone marrow exhaustion.Citation Format: Norman E. Sharpless. Transient CDK4/6 inhibition protects hematopoietic progenitors from chemotherapy-induced exhaustion. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Thera...

Source: Molecular Cancer Research - November 9, 2016 Category: Cancer & Oncology Authors: Sharpless, N. E. Tags: Getting out of Cycle: G0 and Senescence: Oral Presentations - Invited Abstracts Source Type: research