Abstract
Primary and acquired drug resistance imposes a major threat to achieving optimized clinical outcomes during cancer treatment. Aberrant changes in epigenetic modifications are closely involved in drug resistance of tumor cells. 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 the CRISPR interference technology, we identified the second intron of IncRNA, PVT1, as a unique bona fide gained enhancer that restored MYC transcription independent of BRD4 recruitment in leukemia. A combined BETi and CDK7 inhibitor treatment abolished MYC transcription by impeding RNAPII loading without affecting PVT1-mediated chromatin looping at the MYC locus in BETi-resistant leukemia cells. 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
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