Abstract
Primary and acquired drug resistance is a major challenge to achieving optimized clinical outcomes during cancer treatment which can arise from transcription reactivation, bypass and alteration during anticancer treatment [1-3]. Epigenetic dysregulation is emerging as a crucial component involved in drug resistance. Transcriptional adaptation during drug treatment is often mediated by inducible histone modifications, especially histone H3 lysine 27 acetylation (H3K27ac) at the distal enhancer elements, thus activating the transcription of drug resistance-associated genes [4-6]. BRD4 (bromodomain-containing protein 4), a member of the bromodomain and extra-terminal domain (BET) family, acts as a chromatin reader to regulate transcription by linking histone acetylation and core components of the transcriptional apparatus [7]. BET inhibitors (BETi), as exemplified by JQ1 and I-BET151, have been shown to suppress the growth of multiple types of tumor both in vitro and in vivo [8]. However, drug resistance associated with BETi becomes one of the major hurdles hampering the clinical applications of these promising drug candidates [8, 9]. Using BET inhibitor (BETi) resistant leukemia cells as a model system, we demonstrated herein that genome-wide enhancer remodeling played a pivotal role in driving therapeutic resistance via compensational re-expression of pro-survival genes. Capitalizing on CRISPR interference, we identified the second intron of IncRNA, PVT1, as a unique bona fidegained enhancer that restored MYCtranscription independent of BRD4 recruitment. A combined BETi and CDK7 inhibitor treatment abolished MYC transcription by impeding RNAPII loading without affecting PVT1-mediated chromatin looping at the MYClocus in BETi-resistant leukemia cells. Furthermore, recipient mice transferred with BETi-resistant murine MLL-AF9 AML cells receiving the combination treatment showed the most effective therapeutic outcomes, as characterized by prolonged overall survival and reduced tumor burdens in the spleen and bone marrow. Together, our findings have established the feasibility of targeting enhancer plasticity to overcome drug resistance associated with epigenetic therapies.
Highlights
Primary and acquired drug resistance imposes a major threat to achieving optimized clinical outcomes during cancer treatment
Enhancer reprogramming during tumorigenesis can increase the fitness of tumor cells toward anti-tumor therapy[44,45], and provide an alternative strategy for tumor cells to maintain the expression of key genes for survival and growth during drug treatment[46]
Recent studies have shown the promise of targeting enhancer plasticity with combinatorial regimes in various BETiresistant tumor cells, including T-lineage acute lymphoblastic leukemia (T-ALL), triple negative breast cancer (TNBC), and neuroblastoma[23,24,47]
Summary
Enhancer remodeling might be one of the common mechanisms exploited by multiple BETi-resistant tumor cells to drive transcriptional reprogramming. Given that CDK7 inhibitors have been shown to suppress prooncogenic transcription by targeting enhancers in tumor cells[30,31,32,33,34,35], we envisioned that dual inhibition of BRD4 and CDK7 might synergize to suppress the growth of BETi-resistant leukemia cells to overcome resistance. To validate this possibility, we carried out a well-established combinatorial assay on leukemia cells with increasing doses of I-BET151 (a BRD4 inhibitor) and/or THZ1 (a CDK7 inhibitor). Upon dual inhibition of BRD4 and CDK7 using the combination of I-BET151 and THZ1, we observed a strong synergistic lethality in K562 and Jurkat leukemia cells (Fig. 2a, b), but not in OCI-AML2 cells that are highly sensitive to
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
