CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors

Schettini, Francesco; Santo, Irene De; Rea, Carmen G.; Placido, Pietro De; Formisano, Luigi; Giuliano, Mario; Arpino, Grazia; Laurentiis, Michelino De; Puglisi, Fabio; Placido, Sabino De; Mastro, Lucia Del

doi:10.3389/fonc.2018.00608

Cited by 167 publications

(141 citation statements)

References 72 publications

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“…The former approach demonstrated an exquisite selectivity toward CDK9, and the latter revealed an exclusive, strong engagement of CDK9 and CDK10. So far, such a level of selectivity has only been achieved with CDK4/CDK6 inhibitors (palbociclib, alvociclib, ribociclib), the first approved CDK inhibitors that are meeting a great success in metastatic breast cancer treatment (Schettini et al, 2018). Hence, NVP-2 represents a highly promising starting point to design analogs that will hopefully inhibit selectively CDK10/CycM.…”

Section: Discussionmentioning

confidence: 99%

“…However, most inhibitors that have been developed so far inhibit multiple CDKs (not mentioning other protein kinases) and they have produced disappointing outcomes in clinical trials, partly due to their lack of specificity (Asghar et al, 2015). The recent tremendous therapeutic success of highly selective CDK4/6 inhibitors against hormone-dependent metastatic breast cancers and their promising activity against other solid tumors (Schettini et al, 2018) have demonstrated that CDKs can be valuable therapeutic targets, provided that they are addressed by selective molecules.…”

Section: Introductionmentioning

confidence: 99%

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Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

et al. 2020

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Cyclin-dependent kinases (CDKs) constitute a family of 20 serine/threonine protein kinases that play pivotal roles in the regulation of numerous important molecular and cellular processes. CDKs have long been considered promising therapeutic targets in a variety of pathologies, and the recent therapeutic success of CDK4/6 inhibitors in breast cancers has renewed interest in their therapeutic potential. Small-molecule inhibitors have been identified for every human CDK, except for CDK10. The only recent discovery of an activating cyclin (CycM) for CDK10 enabled us to identify its first phosphorylation substrates and gain insights into its biological functions. Yet, our knowledge of this kinase remains incomplete, despite it being the only member of its family that causes severe human developmental syndromes, when mutated either on the cyclin or the CDK moiety. CDK10 small-molecule inhibitors would be useful in exploring the functions of this kinase and gauging its potential as a therapeutic target for some cancers. Here, we report the identification of an optimized peptide phosphorylation substrate of CDK10/CycM and the development of the first homogeneous, miniaturized CDK10/CycM in vitro kinase assay. We reveal the ability of known CDK inhibitors, among which clinically tested SNS-032, riviciclib, flavopiridol, dinaciclib, AZD4573 and AT7519, to potently inhibit CDK10/CycM. We also show that NVP-2, a strong, remarkably selective CDK9 inhibitor is an equally potent CDK10/CycM inhibitor. Finally, we validate this kinase assay for applications in high-throughput screening campaigns to discover new, original CDK10 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

et al. 2020

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“…Our data suggest RPS27 as a potential prognostic marker in cutaneous melanoma and a plausible predictive biomarker of multidrug sensitivity. Some of these compounds, such as CDK4/6 inhibitors, have recently been tested clinically for the treatment of melanoma and other solid tumors (Jerby‐Arnon et al, ; Schettini et al, ). Interestingly, we found that the bimodal RPS27 expression extends to 10 other human cancer types in addition to melanoma.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of RPS27 mutations and expression in melanoma

Floristán

Morales

Hanniford

et al. 2019

Pigment Cell Melanoma Res

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Next‐generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited depth of coverage of whole‐genome sequencing performed on cutaneous melanoma samples make the identification of novel driver mutations difficult. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27‐low patients displaying worse prognosis. In vitro characterization of RPS27‐high and RPS27‐low melanoma cell lines, as well as loss‐of‐function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression, and in those, similarly to melanoma, RPS27‐low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.

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“…Ribociclib, palbociclib and abemaciclib bind to CDK4 and 6 ATP pocket, which induces CDK4/6 inhibition. These drugs are used in metastatic hormone receptor positive, HER2negative breast cancer together with aromatase inhibitors in first line or with fulvestrant as second line (216). The resistance mechanisms where NF-κB was involved were obtained from data in glioblastoma cell lines where it was found that abemaciclib treatment was ineffective to inhibit cell proliferation.…”

Section: Cdk4/6 Inhibitorsmentioning

confidence: 99%

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

et al. 2020

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Breast cancer is the most frequently diagnosed cancer and the principal cause of mortality by malignancy in women and represents a main problem for public health worldwide. Tumor necrosis factor α (TNFα) is a pro-inflammatory cytokine whose expression is increased in a variety of cancers. In particular, in breast cancer it correlates with augmented tumor cell proliferation, higher malignancy grade, increased occurrence of metastasis and general poor prognosis for the patient. These characteristics highlight TNFα as an attractive therapeutic target, and consequently, the study of soluble and transmembrane TNFα effects and its receptors in breast cancer is an area of active research. In this review we summarize the recent findings on TNFα participation in luminal, HER2-positive and triple negative breast cancer progression and metastasis. Also, we describe TNFα role in immune response against tumors and in chemotherapy, hormone therapy, HER2-targeted therapy and anti-immune checkpoint therapy resistance in breast cancer. Furthermore, we discuss the use of TNFα blocking strategies as potential therapies and their clinical relevance for breast cancer. These TNFα blocking agents have long been used in the clinical setting to treat inflammatory and autoimmune diseases. TNFα blockade can be achieved by monoclonal antibodies (such as infliximab, adalimumab, etc.), fusion proteins (etanercept) and dominant negative proteins (INB03). Here we address the different effects of each compound and also analyze the use of potential biomarkers in the selection of patients who would benefit from a combination of TNFα blocking agents with HER2-targeted treatments to prevent or overcome therapy resistance in breast cancer.

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CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors

Cited by 167 publications

References 72 publications

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

Development of a CDK10/CycM in vitro Kinase Screening Assay and Identification of First Small-Molecule Inhibitors

Functional analysis of RPS27 mutations and expression in melanoma

Tumor Necrosis Factor α Blockade: An Opportunity to Tackle Breast Cancer

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