CRISPR/Cas9 screening identifies a kinetochore‐microtubule dependent mechanism for Aurora‐A inhibitor resistance in breast cancer

Chen, Ailin; Wen, Shulin; Liu, Fang; Zhang, Zijian; Liu, Meiling; Wu, Yuanzhong; He, Bin; Yan, Min; Kang, Tiebang; Lam, Eric; Wang, Zifeng; Liu, Quentin

doi:10.1002/cac2.12125

Cited by 27 publications

(19 citation statements)

References 65 publications

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“…However, combining a Haspin inhibitor (CHR-6494) with alisertib reduced cell viability favorably and inhibited its in vivo and in vitro tumor growth by causing extreme microtubule depolymerization, and along with other mechanisms, the mitotic process was disrupted, brought forth by the obliteration of the recruitment of Aurora-B and mitotic centromere associated kinesin to the centromeres. This ultimately demonstrates the use of CHR-6494 as a combinational drug with alisertib and its promising therapeutic benefits [176]. Future implications of breast cancer genes studied using CRISPR/Cas9 are summarized in Table 6.…”

Section: Synthetic Lethality Screensmentioning

confidence: 86%

New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer

Ahmed

Daoud

Mohamed

et al. 2021

Genes

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Breast cancer is one of the most prevalent forms of cancer globally and is among the leading causes of death in women. Its heterogenic nature is a result of the involvement of numerous aberrant genes that contribute to the multi-step pathway of tumorigenesis. Despite the fact that several disease-causing mutations have been identified, therapy is often aimed at alleviating symptoms rather than rectifying the mutation in the DNA sequence. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 is a groundbreaking tool that is being utilized for the identification and validation of genomic targets bearing tumorigenic potential. CRISPR/Cas9 supersedes its gene-editing predecessors through its unparalleled simplicity, efficiency and affordability. In this review, we provide an overview of the CRISPR/Cas9 mechanism and discuss genes that were edited using this system for the treatment of breast cancer. In addition, we shed light on the delivery methods—both viral and non-viral—that may be used to deliver the system and the barriers associated with each. Overall, the present review provides new insights into the potential therapeutic applications of CRISPR/Cas9 for the advancement of breast cancer treatment.

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Section: Synthetic Lethality Screensmentioning

confidence: 86%

New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer

Ahmed

Daoud

Mohamed

et al. 2021

Genes

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“…M phase cells were synchronized using nocodazole [ 48 ] unless otherwise indicated. Briefly, cells were treated with 100 ng/ml nocodazole for 14–16 h. For western blot and ATP concentration testing, mitosis cells were collected after shake-off.…”

Section: Methodsmentioning

confidence: 99%

“…When the tumors reached ~3 mm in diameter, mice were randomized into four groups for treatment with alisertib only (alisertib 15 mg/kg/day), metformin only (metformin 300 mg/kg/day), a combination of metformin and alisertib (metformin 300 mg/kg/day, alisertib 15 mg/kg/day), or a vehicle (1% β-Cyclodextrin with 1% sodium bicarbonate) via oral gavage. Tumor sizes were measured every 2 days and the volumes were calculated by a previously used equation V = (length × width 2 )/2 [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

“…When the tumors reached ~3 mm in diameter, mice were randomized into groups for treatment with alisertib only (alisertib 15 mg/kg/day), a combination of metformin and alisertib (metformin 300 mg/kg/day, alisertib 15 mg/kg/day), or a vehicle (1% β-Cyclodextrin with 1% sodium bicarbonate) via oral gavage. Tumor sizes were measured every 2 days and the volumes were calculated by a previously used equation V = (length × width 2 )/2 [ 48 ]. Mice were injected intraperitoneally with luciferin (3 mg per mouse, YEASEN, HB181121) and imaged using an in vivo imaging system (Bruker MI) on the 14th day after injection.…”

Section: Methodsmentioning

confidence: 99%

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Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition

et al. 2021

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Uncontrolled mitosis is one of the most important features of cancer, and mitotic kinases are thought to be ideal targets for anticancer therapeutics. However, despite numerous clinical attempts spanning decades, clinical trials for mitotic kinase-targeting agents have generally stalled in the late stages due to limited therapeutic effectiveness. Alisertib (MLN8237) is a promising oral mitotic aurora kinase A (AURKA, Aurora-A) selective inhibitor, which is currently under several clinical evaluations but has failed in its first Phase III trial due to inadequate efficacy. In this study, we performed genome-wide CRISPR/Cas9-based screening to identify vulnerable biological processes associated with alisertib in breast cancer MDA-MB-231 cells. The result indicated that alisertib treated cancer cells are more sensitive to the genetic perturbation of oxidative phosphorylation (OXPHOS). Mechanistic investigation indicated that alisertib treatment, as well as other mitotic kinase inhibitors, rapidly reduces the intracellular ATP level to generate a status that is highly addictive to OXPHOS. Furthermore, the combinational inhibition of mitotic kinase and OXPHOS by alisertib, and metformin respectively, generates severe energy exhaustion in mitotic cells that consequently triggers cell death. The combination regimen also enhanced tumor regression significantly in vivo. This suggests that targeting OXPHOS by metformin is a potential strategy for promoting the therapeutic effects of mitotic kinase inhibitors through the joint targeting of mitosis and cellular energy homeostasis.

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“…Breast cancer characteristically displays uncontrolled or abnormal cell proliferation due to excessive microtubule synthesis [11,12]. Knowledge and understanding of this intrinsic property have resulted in the development of chemotherapeutic regimens that act by interfering with the microtubule assembly or disassembly [13].…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Newly Synthesized Acrylamide Derivatives as Potential Chemotherapeutic Agents against MCF-7 Breast Cancer Cell Line Lodged on PEGylated Bilosomal Nano-Vesicles for Improving Cytotoxic Activity

et al. 2021

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Cancer is a multifaceted disease. With the development of multi drug resistance, the need for the arousal of novel targets in order to avoid these drawbacks increased. A new series of acrylamide derivatives was synthesized from starting material 4–(furan–2–ylmethylene)–2–(3,4,5–trimethoxyphenyl)oxazol–5(4H)–one (1), and they are evaluated for their inhibitory activity against b-tubulin polymerization. The target molecules 2–5 d were screened for their cytotoxic activity against breast cancer MCF-7 cell line. The results of cytotoxicity screening revealed that compounds 4e and 5d showed good cytotoxic profile against MCF-7 cells. Compounds 4e produced significant reduction in cellular tubulin with excellent b-tubulin polymerization inhibition activity. In addition, compound 4e exhibited cytotoxic activity against MCF-7 cells by cell cycle arrest at pre-G1 and G2/M phases, as shown by DNA flow cytometry assay. Aiming to enhance the limited aqueous solubility and, hence, poor oral bioavailability of the prepared lead acrylamide molecule, 4e-charged PEGylated bilosomes were successfully fabricated via thin film hydration techniques as an attempt to improve these pitfalls. Twenty-three full factorial designs were manipulated to examine the influence of formulation variables: types of bile salt including either sodium deoxy cholate (SDC) or sodium tauro cholate (STC), amount of bile salt (15 mg or 30 mg) and amount of DSPE–mPEG-2000 amount (25 mg or 50 mg) on the characteristics of the nanosystem. The F7 formula of entrapment efficiency (E.E% = 100 ± 5.6%), particle size (PS = 280.3 ± 15.4 nm) and zeta potential (ZP = −22.5 ± 3.4 mv) was picked as an optimum formula with a desirability value of 0.868. Moreover, prominent enhancement was observed at the compound’s cytotoxic activity (IC50 = 0.75 ± 0.03 µM) instead of (IC50 = 2.11 ± 0.19 µM) for the unformulated 4e after being included in the nano-PEGylated bilosomal system.

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CRISPR/Cas9 screening identifies a kinetochore‐microtubule dependent mechanism for Aurora‐A inhibitor resistance in breast cancer

Cited by 27 publications

References 65 publications

New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer

New Insights into the Therapeutic Applications of CRISPR/Cas9 Genome Editing in Breast Cancer

Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition

Design and Synthesis of Newly Synthesized Acrylamide Derivatives as Potential Chemotherapeutic Agents against MCF-7 Breast Cancer Cell Line Lodged on PEGylated Bilosomal Nano-Vesicles for Improving Cytotoxic Activity

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