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MDM2 inhibition in chronic lymphocytic leukemia
incidence of clonal evolution leading to ibrutinib resist- ance due to mutations in BTK and PLCG2 have been reported in patients progressing on treatment.52
Continued preclinical studies to develop innovative therapeutic strategies for CLL therefore remain a high pri- ority. In particular, new agents promoting CLL cell apop- tosis with limited toxicity to normal cells represent an attractive therapeutic strategy for CLL, which is a disease of elderly patients who would benefit from the use of compounds with a therapeutic window associated with minimal effects on normal cells. Moreover, given the clin- ical heterogeneity of CLL, there is a constant need to iden- tify treatment strategies that can be effective also in the most aggressive subtypes of this disease. In our cohort, RG7388 significantly decreased the viability of CLL cells isolated from patients in different poor prognosis sub- groups, including cases with advanced-stage disease, cases with unmutated IGHV genes and cases with 11q deletion and trisomy 12, which are usually more prone to progres- sion. This indicates that inhibiting the p53-MDM2 inter- action is a promising treatment strategy to explore for high-risk CLL patients with functional p53.
Taken together, our data demonstrate that MDM2
inhibitors induce a pro-apoptotic response in cells from patients with both low- and high-risk subtypes of CLL, at doses which show a lesser effect on normal blood cells and hematopoietic stem cells. This therapeutic window supports the clinical evaluation of new-generation, non- genotoxic MDM2 inhibitors, used in combined treatment strategies with other targeted therapies for the treatment of CLL.
Acknowledgments
This study was supported by Bloodwise (grant # 13034), the JGW Patterson Foundation (grant # BH152495) and the Newcastle Healthcare Charity (grant # BH152694).
The authors gratefully acknowledge Newcastle University/Astex Pharmaceuticals Alliance and CRUK which funded the Drug Discovery Programme at the Northern Institute for Cancer Research, Newcastle University for their support and encouragement.
The authors would also like to thank Jane Cole for recruiting patients and providing clinical information, Dr Kenneth Rankin for providing bone marrow samples, Dr Sally Hall for providing blood samples from healthy donors and all the CLL patients for generously donating samples.
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