Aberrant CDK4 Amplification in Refractory Rhabdomyosarcoma as Identified by Genomic Profiling

Park, Silvia; Lee, Jeeyun; Do, In‐Gu; Jang, Jiryeon; Rho, Kyoohyoung; Ahn, Seonjoo; Lira, Maruja; Kim, Sung Joo; Kim, Kyoung‐Mee; Mao, Mao; Oh, Ensel; Kim, Yu Jin; Kim, Young Tae; Choi, Yoon‐La

doi:10.1038/srep03623

Cited by 26 publications

(13 citation statements)

References 37 publications

(41 reference statements)

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“…Deregulated cyclin D1 protein expression, gene translocation and gene amplification are observed in many tumour types 50-54 , and a plethora of functional data support the specific oncogenic activity of cyclin D1 (REFS 17,18,51). Furthermore, amplification of CDK4 and CDK6 is observed in several different types of cancer 55,56 . Importantly, the distinct mechanisms of pathway dysregulation are mutually exclusive and are frequently tumour type-specific.…”

Section: The Biology Of Cdksmentioning

confidence: 99%

The history and future of targeting cyclin-dependent kinases in cancer therapy

Asghar

Witkiewicz

Turner

et al. 2015

Nat Rev Drug Discov

1,425

1,323

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Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

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Section: The Biology Of Cdksmentioning

confidence: 99%

The history and future of targeting cyclin-dependent kinases in cancer therapy

Asghar

Witkiewicz

Turner

et al. 2015

Nat Rev Drug Discov

1,425

1,323

View full text Add to dashboard Cite

show abstract

“…In human cancers, owing to various genetic and epigenetic events, CDKs are often overexpressed and/or overactive, bringing about loss of checkpoint integrity and ultimately resulting in uncontrolled cell proliferation [27, 50–53]. For example, the cyclin D/CDK4/CDK6/RB pathway is hyperactive in various malignancies, such as melanoma, glioblastoma, osteosarcoma, lymphomas, breast and cervical cancers, squamous cell cancer, etc [54].…”

Section: The Biology and Deregulation Of Cdks In Human Cancersmentioning

confidence: 99%

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

et al. 2016

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Overexpression and/or hyperactivation of cyclin-dependent kinases (CDKs) are common features of most cancer types. CDKs have been shown to play important roles in tumor cell proliferation and growth by controlling cell cycle, transcription, and RNA splicing. CDK4/6 inhibitor palbociclib has been recently approved by the FDA for the treatment of breast cancer. CDK11 is a serine/threonine protein kinase in the CDK family and recent studies have shown that CDK11 also plays critical roles in cancer cell growth and proliferation. A variety of genetic and epigenetic events may cause universal overexpression of CDK11 in human cancers. Inhibition of CDK11 has been shown to lead to cancer cell death and apoptosis. Significant evidence has suggested that CDK11 may be a novel and promising therapeutic target for the treatment of cancers. This review will focus on the emerging roles of CDK11 in human cancers, and provide a proof-of-principle for continued efforts toward targeting CDK11 for effective cancer treatment.

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“…A particularly aggressive subset of fusion-positive RMS tumors was found to harbor amplification of chromosomal region 12q13-q14 (9, 10). This region, which contains the cyclin-dependent kinase 4 ( CDK4 ) locus, was amplified in ~25% of PAX3-FOXO1 -positive tumors and ~4% of PAX7-FOXO1 -positive tumors (9).…”

Section: Introductionmentioning

confidence: 99%

CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma

Olanich

Sun

Hewitt

et al. 2015

Clinical Cancer Research

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Purpose Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and includes a PAX3- or PAX7-FOXO1 fusion-positive subtype. Amplification of chromosomal region 12q13-q14, which contains the CDK4 proto-oncogene, was identified in an aggressive subset of fusion-positive RMS. CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma, suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS. Experimental Procedures We examined the biological consequences of CDK4 knockdown, CDK4 overexpression, and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts. Results Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and non-amplified fusion-positive RMS cells via G1-phase cell cycle arrest. This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression. Significant differences in E2F target expression, cell cycle distribution, proliferation, or transformation were not observed in RMS cells overexpressing CDK4. Treatment with LEE011 phenocopied CDK4 knockdown, decreasing viability, RB phosphorylation, and E2F-responsive gene expression and inducing G1-phase cell cycle arrest. Though all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition, there was diminished sensitivity associated with CDK4 amplification and overexpression. This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and non-amplified fusion-positive RMS. Conclusions Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB-E2F-mediated G1-phase cell cycle progression, proliferation, and transformation in fusion-positive RMS. Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition.

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Aberrant CDK4 Amplification in Refractory Rhabdomyosarcoma as Identified by Genomic Profiling

Cited by 26 publications

References 37 publications

The history and future of targeting cyclin-dependent kinases in cancer therapy

The history and future of targeting cyclin-dependent kinases in cancer therapy

The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer

CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma

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