Enhancing the efficacy of glycolytic blockade in cancer cells via RAD51 inhibition.
The authors acknowledge the following individuals from The Jackson Laboratory Scientific Services: the Flow Cytometry Service: William Schott and Ted Duffy for their technical support; and the PDX R&D Core: Dr. Kin-Hoe Chow (manager), Amy Lambert, Ed Keniston, and Srijoy Gupta for xenograft studies. In addition, the authors acknowledge Stephen Sampson for assistance in manuscript preparation, Dr. Michael Wiles for assistance in CRISPr construct generation, Dr. Heidi Kocalis for imaging consultation, and Dr. Ewelina Bolcun-Filas for critical reading of the paper.
Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor. Next, we tested the cancer-cell specificity of a therapeutic compound using the MEC1 cell line, a chronic lymphocytic leukemia (CLL) cell line that expresses activation induced cytidine deaminase (AID). We show that MEC1 cells, are susceptible to 4,4'-Diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), a specific RAD51 inhibitor. We then combine 2DG and DIDS, each at a lower dose and demonstrate that this combination is more efficacious than fludarabine, the current standard- of- care treatment for CLL. This suggests that the therapeutic blockade of glycolysis together with the therapeutic inhibition of RAD51-dependent homologous recombination can be a potentially beneficial combination for targeting AID positive cancer cells with minimal adverse effects on normal tissue.
IMPLICATIONS: Combination therapy targeting glycolysis and specific RAD51 function shows increased efficacy as compared to standard of care treatments in leukemias.