Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs

Hugle, Manuela; Belz, Katharina; Fulda, Simone

doi:10.1038/cdd.2015.59

Cited by 49 publications

(62 citation statements)

References 31 publications

(47 reference statements)

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“…Moreover, CN gains of genes involved in responses to ROS, glucose uptake/catabolism, and biosynthetic processes may help in facing ROS accumulation, which causes oxidative DNA damage, 47 and support energy metabolism in A-AML. Candidate strategies include a combination of microtubule depolymerizing drugs and PLK1 inhibitors, which drove BCL2 inactivation in a rhabdomyosarcoma model, 48 dual topoisomerase I and CHK1 inhibition, which achieved a curative response in the context of decreased expression of RAD50 in carcinoma, 49 and simultaneous targeting of glycolytic metabolism and Aurora kinases, which killed AML cells. Although drugs inhibiting some of these cellular functions have shown poor activity (eg, NCT00666588 and NCT00830518) and/or an adverse risk-benefit ratio (eg, NCT01721876 and NCT02030405) in previous trials, pretreatment omics analyses may favor the selection of patient subgroups that will likely benefit from these targeted agents in the near future.…”

Section: Discussionmentioning

confidence: 99%

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

Simonetti

Padella

Valle

et al. 2018

Cancer

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Background Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis. Methods To understand the molecular bases of aneuploid acute myeloid leukemia (A‐AML), this study examined the genomic profile in 42 A‐AML cases and 35 euploid acute myeloid leukemia (E‐AML) cases. Results A‐AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E‐AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A‐AML, which was associated with a 3‐gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A‐AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E‐AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression. Conclusions These findings indicate that aneuploidy‐related and leukemia‐specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

Simonetti

Padella

Valle

et al. 2018

Cancer

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“…The combination of another PLK1 small molecule kinase inhibitor BI 6727 with vincristine showed synergistic inhibition effects in Ewing sarcoma through the induction of mitochondrial pathway apoptosis and triggered mitotic arrest 72 . In rhabdomyosarcoma, BI 2536 and BI 6727 also synergistically induced apoptosis and mitotic arrest with co-treatment with vincristine in vitro and in vivo 75 . The group also confirmed that the combination of BI 2536 with eribulin showed synergistic inhibition effects in rhabdomyosarcoma 71 .…”

Section: Targeting Serine/threonine Protein Kinases To Reverse Mdr Inmentioning

confidence: 93%

Targeting protein kinases to reverse multidrug resistance in sarcoma

Chen

Shen

Choy

et al. 2016

Cancer Treatment Reviews

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Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma.

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“…In contrast to rigosertib, volasertib induces oncogenic AKT and ERK signalling and synergizes with AKT or mTOR inhibition in vitro 212 . Volasertib demonstrated impressive anti-tumour activity in xenograft models of neuroblastoma (as monotherapy) 213 , ALL (as monotherapy and in combination with cytarabine or quizartinib) 213, 214 , breast cancer (in combination with fulvestrant) 215 and rhabdomyosarcoma (with vincristine) 216 . A clinical phase II trial compared volasertib in combination with low-dose cytarabine versus cytarabine alone for older patients with AML (TABLE 3).…”

Section: Targeting Of Other Cell Cycle Proteinsmentioning

confidence: 99%

“…Caused tumour regression in combination with cytarabine or FLT3 inhibitor quizartinib in AML 214 and with vincristine in rhabdomyosarcoma xenografts 216 …”

Section: Figurementioning

confidence: 99%

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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Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs

Cited by 49 publications

References 31 publications

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery

Targeting protein kinases to reverse multidrug resistance in sarcoma

Cell cycle proteins as promising targets in cancer therapy

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