A Combination Strategy Targeting Enhancer Plasticity Exerts Synergistic Lethality Against Beti-Resistant Leukemia Cells Academic Article uri icon

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. References 1. Mansoori, B., et al., The Different Mechanisms of Cancer Drug Resistance: A Brief Review.Adv Pharm Bull, 2017. 7(3): p. 339-348. 2. Konieczkowski, D.J., C.M. Johannessen, and L.A. Garraway, A Convergence-Based Framework for Cancer Drug Resistance.Cancer Cell, 2018. 33(5): p. 801-815. 3. Holohan, C., et al., Cancer drug resistance: an evolving paradigm.Nat Rev Cancer, 2013. 13(10): p. 714-26. 4. Zanconato, F., et al., Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4.Nat Med, 2018. 24(10): p. 1599-1610. 5. Takeda, D.Y., et al., A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer.Cell, 2018. 174(2): p. 422-432 e13. 6. Chen, X., et al., A novel enhancer regulates MGMT expression and promotes temozolomide resistance in glioblastoma.Nat Commun, 2018. 9(1): p. 2949. 7. Jang, M.K., et al., The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription.Mol Cell, 2005. 19(4): p. 523-34. 8. Andrieu, G., A.C. Belkina, and G.V. Denis, Clinical trials for BET inhibitors run ahead of the science.Drug Discov Today Technol, 2016. 19: p. 45-50. 9. Pervaiz, M., P. Mishra, and S. Gunther,Bromodomain Drug Discovery - the Past, the Present, and the Future.Chem Rec, 2018. 18(12): p. 1808-1817. Disclosures No relevant conflicts of interest to declare.

published proceedings

  • Blood

author list (cited authors)

  • Guo, L., Li, J., Zeng, H., Guzman, A., Li, T., Lee, M., ... Huang, Y.

citation count

  • 0

complete list of authors

  • Guo, Lei||Li, Jia||Zeng, Hongxiang||Guzman, Anna||Li, Tingting||Lee, Minjung||Zhou, Yubin||Stephan, Clifford||Davies, Peter JA||Goodell, Margaret||Sun, Deqiang||Dawson, Mark A||Huang, Yun

publication date

  • November 2019

published in