Human ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1

Wu, Chung Pu; Hsieh, Chi-Hsun; Hsiao, Sung Han; Luo, Shuang; Su, Ching Ya; Li, Yan Qing; Huang, Yang; Huang, Chiun Wei; Hsu, Sheng Chieh

doi:10.1021/acs.molpharmaceut.5b00312

Cited by 29 publications

(30 citation statements)

References 64 publications

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“…Based on in vitro data it was suggested that p53-negative cancers would be particularly sensitive to PLK1 inhibition 221 . Importantly, overexpression of the ABC transporter ABCB1 (P-glycoprotein) conferred resistance to volasertib treatment in vitro , supporting future co-administration of ABCB1 inhibitors to improve clinical responses 222 .…”

Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 94%

Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 94%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…The results from these experiments indicated that BI6727 reversed ABC‐B1‐mediated MDR by inhibition of the ATP hydrolysis, while volasertib could also act as a competitive inhibitor substrate for the ABC‐G2 transporter . In contrast, Wu et al . found that overexpression of the ABC‐B1 transporter leads to cellular resistance to volasertib treatment.…”

Section: Volasertib Monotherapymentioning

confidence: 95%

“…The ability of volasertib to restore drug sensitivity was also investigated, but the Plk1 inhibitor did not significantly affect ABC‐B1‐mediated resistance to doxorubicin, colchicine, or paclitaxel at the concentrations tested. Although low concentrations of volasertib competitively inhibit ABC‐B1‐mediated transport, these concentrations were insufficient to reverse ABC‐B1‐mediated drug resistance . Further studies are needed to clarify the discrepancy between the studies of To et al.…”

Section: Volasertib Monotherapymentioning

confidence: 95%

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Bossche

Lardon

Deschoolmeester

et al. 2016

Medicinal Research Reviews

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Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

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“…Overexpression of the ATP-binding cassette (ABC) drug transporter ABCB1 has been shown to reduce the effect of chemotherapeutic agents on cancer cells by utilizing ATP hydrolysis to transport the drugs out of cancer cells (68). Recently, Wu and colleagues found that the resistance is conferred via this mode of action with volasertib (69). Therefore, using a modulator of ABCB1 as a cotreatment in future trials may be an effective method to prevent this route of resistance.…”

Section: Plk1 As a Drug Targetmentioning

confidence: 99%

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge

Ndiaye

Liu

et al. 2016

Molecular Cancer Therapeutics

338

272

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Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management. Plk1 inhibition has been shown to cause mitotic block and apoptosis of cells with higher mitotic index and therefore higher Plk1 expression. The potential of Plk1 inhibitors as cancer therapeutics has been widely investigated. However, a complete understanding of Plk1 biology/mechanism is yet to be fully achieved. Resistance to certain chemotherapeutic drugs has been linked to Plk1 overexpression, and Plk1-mediated mitotic events such as microtubule rearrangement have been found to reduce the efficacy of chemotherapeutic agents. The Plk1 inhibitor, volasertib, has shown considerable promise in clinical studies, having reached phase III trials. However, preclinical success with Plk1 inhibitors has not translated well into clinical success. In our view, combined therapies targeting other relevant pathways together with Plk1 may be vital to combat issues observed with monotherapy, especially resistance. In addition, research should also be directed towards understanding the mechanisms of Plk1 and designing additional next generations of specific, potent Plk1 inhibitors to target cancer.

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Human ATP-Binding Cassette Transporter ABCB1 Confers Resistance to Volasertib (BI 6727), a Selective Inhibitor of Polo-like Kinase 1

Cited by 29 publications

References 64 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

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