scholarly journals A Combination Strategy Targeting Enhancer Plasticity Exerts Synergistic Lethality Against Beti-Resistant Leukemia Cells

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5053-5053
Author(s):  
Lei Guo ◽  
Jia Li ◽  
Hongxiang Zeng ◽  
Anna Guzman ◽  
Tingting Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Rna Polymerase Ii ◽  
Conflicts Of Interest ◽  
Leukemia Cells ◽  
Cancer Drug ◽  
Distal Enhancer ◽  
Combination Strategy ◽  
Cancer Drug Resistance ◽  
Bet Inhibitors

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.

scholarly journals Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

2021 ◽  
Vol 14 (5) ◽  
pp. 470
Author(s):  
Nirmala Tilija Pun ◽  
Chul-Ho Jeong
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Drug Repurposing ◽  
Synergistic Action ◽  
Cancer Drug ◽  
Cancer Cell Proliferation ◽  
Cancer Drug Resistance ◽  
Anti Cancer

Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

scholarly journals Interrogating Novel Bromodomain Inhibition Resistance Mechanism in Mllr Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 26-26
Author(s):  
Chunliang Li ◽  
Shaela Wright ◽  
Jianzhong Hu ◽  
Yang Zhang ◽  
Judith Hyle ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Adaptor Protein ◽  
Leukemia Cells ◽  
Resistance Phenotype ◽  
Bet Inhibitors ◽  
Resistant Cells

Abstract MLL-rearranged (MLLr) leukemias count for more than 80% of infant leukemia, ~5-10% of B-cell acute lymphoblastic leukemia (B-ALL), and ~10% of acute myeloid leukemia (AML) cases, where they confer a particularly poor outcome. Despite treatment with intensive multi-agent chemotherapy, most MLLr patients achieved an initial remission but ultimately relapsed. Bromo- and Extra-Terminal domain inhibitors (BETi) prevent the progression of many cancer types in preclinical studies, including MLLr leukemia. However, the mechanisms controlling drug response and resistance of BET inhibitors are not well understood. We have addressed this timely, crucial scientific question by completing genetic screens to explore potential BETi resistance mechanisms. By conducting genome-wide and targeted loss-of-function CRISPR screens using MLLr AML cell lines upon BETi treatment including ABBV-744, JQ1, and dBET1, we discovered that Speckle Type POZ (SPOP) gene deficiency leads to significant BETi resistance in in vitro cell culture systems (SEM, OCI-AMl2 and MV4,11), and by in vivo transplantation of human MLLr leukemia SEM cells into immune-deficient mice. However, no BETi resistance phenotype was seen in non-MLLr SPOP-deficient cells. SPOP was previously reported as an adaptor protein to bridge the E3 ubiquitination complex component CUL3 to the substrate proteins BRD4 and MYC in prostate and many other solid cancers. However, in SPOP knockout MLLr leukemia cells, TRIM24, not BRD4 and MYC, was identified as a substrate likely responsible for SPOP's role in drug resistance. Genetically blocking TRIM24 via CRISPR knockout in SPOP-knockout cells reversed the BETi resistance phenotype. Transcriptomic analysis of TRIM24-deficient cells identified the GSK3A signature as the top influenced pathway. Additionally, proteomics expression analysis and a kinase vulnerability CRISPR screen also indicated that resistant cells are sensitive to GSK3B inhibition. Further validation by CRISPR knockout and pharmaceutical blockage of GSK3A/3B (by ChIR-98014) sensitized the SPOP-deficient resistant cells to BETi treatment in vitro. In SEM xenograft models in NSG mice, ABBV-744 or CHIR-98014 minimally impacted human CD45 + leukemia cell proliferation while synergistic treatment significantly reduced the tumor progression. In summary, our data suggest the novel SPOP/TRIM24/GSK3A/3B axis plays an essential role in BETi therapy-resistant leukemia cells. Targeting GSK3A/3B pathways by ChIR-98014 can overcome SPOP-associated BETi resistance in in vivo preclinical models of MLLr leukemia. Successful outcomes following combination therapy using ChIR-98014 and BETi in PDX models would translate to a clinical application that holds the promise to cure MLLr leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Prospective pharmacological methodology for establishing and evaluating anti-cancer drug resistant cell lines

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hoon Yu ◽  
Dong-Jin Kim ◽  
Hye-Young Choi ◽  
So Myoung Kim ◽  
Md. Intazur Rahaman ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Evaluation Methodology ◽  
Cross Resistance ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Resistance Evaluation ◽  
Cancer Drug Resistance ◽  
Anti Cancer

Abstract Background Cell lines are often used to assess the resistance of anticancer drugs when in vivo analysis is not possible. However, the process for establishing anti-cancer drug resistance in cell cultures in vitro and the subsequent method of then evaluating resistance are not clearly established. Traditionally, the IC50 is the most commonly used indicator of resistance evaluation but it cannot represent the effectiveness of anti-cancer drugs in a clinical setting and lacks reliability because it is heavily affected by the cell doubling time. Hence, new indicators that can evaluate anti-cancer drug resistance are needed. Methods A novel resistance evaluation methodology was validated in this present study by establishing sunitinib resistance in renal cell carcinoma cells and assessing the cross-resistance of five different anti-cancer drugs. Results It was confirmed in this present study that the IC50 does not reflect the cell proliferation rates in a way that represents anti-cancer drug resistance. An alternative indicator that can also be clinically meaningful when using in vitro cell line systems is GI100. Additionally, the GR100 allows different cell populations to be calibrated on the same basis when multiple experimental results are compared. Conclusion Since the GR100 has properties that indicate the efficiency of anti-cancer drugs, both the efficacy and GR100 of a particular anti-cancer drug can be used to effectively assess the resistance.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

scholarly journals Recent Progress in Characterizing Long Noncoding RNAs in Cancer Drug Resistance

2019 ◽  
Vol 10 (26) ◽  
pp. 6693-6702 ◽  
Author(s):  
Wenyuan Zhao ◽  
Bin Shan ◽  
Dan He ◽  
Yuanda Cheng ◽  
Bin Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Recent Progress ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Cancer Drug ◽  
Cancer Drug Resistance

Nanoparticle-based drug delivery systems with platinum drugs for overcoming cancer drug resistance

2021 ◽  
Author(s):  
Peng Xie ◽  
Yushu Wang ◽  
Dengshuai Wei ◽  
Lingpu Zhang ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Drug Delivery Systems ◽  
Delivery Systems ◽  
Cancer Drug ◽  
Platinum Drugs ◽  
Effective Strategy ◽  
Platinum Drug ◽  
Cancer Drug Resistance ◽  
Platinum Drug Resistance

The mechanisms of chemoresistance and nanoparticle-based drug delivery systems for platinum drugs were detailed summarized in this review. The current combination therapy provided an effective strategy to overcome the platinum drug resistance.

scholarly journals Correction to Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial

2021 ◽  
Author(s):  
Hai Wang ◽  
Pranay Agarwal ◽  
Gang Zhao ◽  
Guang Ji ◽  
Christopher M. Jewell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Drug Resistance ◽  
Cancer Drug ◽  
Cancer Drug Resistance
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