Preclinical efficacy of CDK7 inhibitor-based combinations against myeloproliferative neoplasms transformed to AML.

Autor:	Fiskus W; MD Anderson Cancer Center, Houston, Texas, United States., Mill CP; MD Anderson Cancer Center, Houston, Texas, United States., Bose P; University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Masarova L; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Pemmaraju N; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Dunbar A; MD Anderson Cancer Center, Houston, Texas, United States., Birdwell C; MD Anderson Cancer Center, Houston, Texas, United States., Davis JA; MD Anderson Cancer Center, Houston, Texas, United States., Das K; UT MD Anderson Cancer Center, Houston, Texas, United States., Hou H; UT MD Anderson Cancer Center, Houston, Texas, United States., Manshouri T; MD Anderson Cancer Center, Houston, Texas, United States., Jain A; Baylor College of Medicine, Houston, Texas, United States., Malovannaya A; Baylor College of Medicine, Houston, Texas, United States., Philip K; MD Anderson Cancer Center, Houston, Texas, United States., Alhamadani N; MD Anderson Cancer Center, Houston, Texas, United States., Matthews A; MD Anderson Cancer Center, Houston, Texas, United States., Lin K; MD Anderson Cancer Center, Houston, Texas, United States., Flores L; UT MD Anderson Cancer Center, Houston, Texas, United States., Loghavi S; The University of Texas, MD Anderson Cancer Center, Houston, Texas, United States., DiNardo CD; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Su X; MD Anderson Cancer Center, Houston, Texas, United States., Rampal RK; Memorial Sloan-Kettering Cancer Center, New York, New York, United States., Bhalla KN; MD Anderson Cancer Center, Houston, Texas, United States.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2024 Nov 19. Date of Electronic Publication: 2024 Nov 19.
DOI:	10.1182/blood.2024026388
Abstrakt:	Rising blast-percentage or secondary (s) AML transformation (sAML) in MPNs leads to JAK inhibitor (JAKi) therapy-resistance and poor survival. Here, we demonstrate that the CDK7 inhibitor (CDK7i) SY-5609 treatment depletes phenotypically-characterized post-MPN-sAML stem/progenitor cells. In the cultured post-MPN sAML SET2 and HEL as well as patient-derived (PD) post-MPN-sAML cells, SY-5609 treatment inhibited growth and induced lethality, while sparing normal cells. RNA-Seq analysis following SY-5609 treatment demonstrated reduced mRNA expressions of MYC, MYB, CDK4/6, PIM1, and CCND1, but increased mRNA levels of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also demonstrated reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase 9 and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced viability of HEL cells. CyTOF analysis of SY-5609-treated PD, post-MPN-sAML stem/progenitor cells showed reduced c-Myc, CDK6 and PU.1, but increased protein levels of CD11b, p21 and cleaved Caspase 3. Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells.  A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML. (Copyright © 2024 American Society of Hematology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu