Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types

Giacomini, Craig P.; Sun, Steven; Varma, Sushama; Shain, A. Hunter; Giacomini, Marilyn M.; Balagtas, Jay; Sweeney, Robert T.; Lai, Everett; Vecchio, Catherine A. Del; Forster, Andrew D.; Clarke, Nicole; Montgomery, Kelli; Zhu, Shirley; Wong, Albert J.; Rijn, Matt van de; West, Robert B.; Pollack, Jonathan R.

doi:10.1371/journal.pgen.1003464

Cited by 105 publications

(87 citation statements)

References 92 publications

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“…However, CDK4 and CDK6 are deregulated in different tumor types, with CDK6 frequently amplified and/or translocated in hematopoietic malignancies. [17][18][19][20][21][22][23][24][25][26][27][28][29] CDK6 is particularly important in AML and acute lymphoblastic leukemia (ALL) driven by mixed-lineage leukemia fusion proteins. [29][30][31] The protumorigenic functions of CDK6, but not of CDK4, go well beyond driving the cell cycle: in lymphoid and myeloid leukemia, CDK6 is part of transcriptional complexes that promote leukemogenesis and tumor formation.…”

Section: Introductionmentioning

confidence: 99%

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

Uras

Walter

Scheicher

et al. 2016

Blood

102

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Key Points• CDK6 directly regulates transcription of FLT3 and PIM1 in a kinase-dependent manner.• CDK6 kinase inhibition impairs not only FLT3-dependent cell growth in vitro but also FLT3-driven leukemogenesis in vivo.Up to 30% of patients with acute myeloid leukemia have constitutively activating internal tandem duplications (ITDs) of the FLT3 receptor tyrosine kinase. Such mutations are associated with a poor prognosis and a high propensity to relapse after remission. FLT3 inhibitors are being developed as targeted therapy for FLT3-ITD 1 acute myeloid leukemia;however, their use is complicated by rapid development of resistance, which illustrates the need for additional therapeutic targets. We show that the US Food and Drug Administration-approved CDK4/6 kinase inhibitor palbociclib induces apoptosis of FLT3-ITD leukemic cells. The effect is specific for FLT3-mutant cells and is ascribed to the transcriptional activity of CDK6: CDK6 but not its functional homolog CDK4 is found at the promoters of the FLT3 and PIM1 genes, another important leukemogenic driver. There CDK6 regulates transcription in a kinase-dependent manner. Of potential clinical relevance, combined treatment with palbociclib and FLT3 inhibitors results in synergistic cytotoxicity. Simultaneously targeting two critical signaling nodes in leukemogenesis could represent a therapeutic breakthrough, leading to complete remission and overcoming resistance to FLT3 inhibitors. (Blood. 2016; 127(23):2890-2902

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Section: Introductionmentioning

confidence: 99%

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

Uras

Walter

Scheicher

et al. 2016

Blood

102

View full text Add to dashboard Cite

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“…However, its function, both in normal physiology and disease, remains poorly defined mainly because of its still unidentified ligand. Chromosomal rearrangements resulting in oncogenic activation of ROS1 have been observed in a subset of patients with glioblastoma (6-9), NSCLC (10)(11)(12)(13)(14), cholangiocarcinoma (15), ovarian cancer (16), angiosarcoma (17), inflammatory myofibroblastic tumors (18), and Spitzoid melanoma (19). To date, interchromosomal translocations or intrachromosomal deletions have resulted in the production of 20 different N-terminal ROS1 fusion genes in a variety of cancers (Table S1).…”

mentioning

confidence: 99%

PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

Zou¹,

Li²,

Engstrom³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

229

184

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Oncogenic c-ros oncogene1 (ROS1) fusion kinases have been identified in a variety of human cancers and are attractive targets for cancer therapy. The MET/ALK/ROS1 inhibitor crizotinib (Xalkori, PF-02341066) has demonstrated promising clinical activity in ROS1 fusion-positive non-small cell lung cancer. However, emerging clinical evidence has shown that patients can develop resistance by acquiring secondary point mutations in ROS1 kinase. In this study we characterized the ROS1 activity of PF-06463922, a novel, orally available, CNS-penetrant, ATP-competitive small-molecule inhibitor of ALK/ROS1. In vitro, PF-06463922 exhibited subnanomolar cellular potency against oncogenic ROS1 fusions and inhibited the crizotinib-refractory ROS1 G2032R mutation and the ROS1 G2026M gatekeeper mutation. Compared with crizotinib and the second-generation ALK/ROS1 inhibitors ceritinib and alectinib, PF-06463922 showed significantly improved inhibitory activity against ROS1 kinase. A crystal structure of the PF-06463922-ROS1 kinase complex revealed favorable interactions contributing to the high-affinity binding. Taken together, our results indicate that PF-06463922 has potential for treating ROS1 fusion-positive cancers, including those requiring agents with CNS-penetrating properties, as well as for overcoming crizotinib resistance driven by ROS1 mutation.PF-06463922 | ROS1 | kinase inhibitor R eceptor tyrosine kinases (RTKs) are vital conduits of extracellular signals that direct cell growth and survival pathways. Unregulated RTK activation through chromosomal rearrangements, point mutations, and gene amplification has been shown to be responsible for the initiation and progression of many cancers. The orphan RTK c-ros oncogene1 (ROS1) normally is expressed transiently in various tissues during development with little to no expression in adult tissues (1). Elevated full-length c-ROS1 expression levels have been observed in 20-30% of patients with nonsmall cell lung cancer (NSCLC) by gene expression profiling (2-4) and in 13% of patients with lung adenocarcinoma using immunohistochemistry (IHC) (5). However, its function, both in normal physiology and disease, remains poorly defined mainly because of its still unidentified ligand. Chromosomal rearrangements resulting in oncogenic activation of ROS1 have been observed in a subset of patients with glioblastoma (6-9), NSCLC (10-14), cholangiocarcinoma (15), ovarian cancer (16), angiosarcoma (17), inflammatory myofibroblastic tumors (18), and Spitzoid melanoma (19). To date, interchromosomal translocations or intrachromosomal deletions have resulted in the production of 20 different N-terminal ROS1 fusion genes in a variety of cancers (Table S1).ROS1 is a distinct receptor with a kinase domain that is phylogenetically related to the anaplastic lymphoma kinase/lymphocyte-specific protein tyrosine kinase (ALK/LTK) and insulin receptor (INSR) RTK families (20), suggesting that tyrosine kinase inhibitors for these receptors could have cross-activity against ROS1. A recent phase I/II cl...

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“…Fip1l1 were chosen as hub gene which was down regulated (p-value= 1.27E-05) in paleturquoise gene module. Tyrosine kinase -FIP1L1-PDGFRalpha is a known fusion gene that play role in chronic eosinophilic leukemia pathogenesis (Giacomini et al, 2013). A similarly study uncovered that FIP1L1/PDGFRA gene fusion caused hypereosinophilic syndrome (Cools et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Identification of Specific Gene Modules in Mouse Lung Tissue Exposed to Cigarette Smoke

Xing

Zhang²,

Lu³

et al. 2015

Asian Pacific Journal of Cancer Prevention

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Background: Exposure to cigarette may affect human health and increase risk of a wide range of diseases including pulmonary diseases, such as chronic obstructive pulmonary disease (COPD), asthma, lung fibrosis and lung cancer. However, the molecular mechanisms of pathogenesis induced by cigarettes still remain obscure even with extensive studies. With systemic view, we attempted to identify the specific gene modules that might relate to injury caused by cigarette smoke and identify hub genes for potential therapeutic targets or biomarkers from specific gene modules. Materials and Methods: The dataset GSE18344 was downloaded from the Gene Expression Omnibus (GEO) and divided into mouse cigarette smoke exposure and control groups. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to construct a gene co-expression network for each group and detected specific gene modules of cigarette smoke exposure by comparison. Results: A total of ten specific gene modules were identified only in the cigarette smoke exposure group but not in the control group. Seven hub genes were identified as well, including Fip1l1, Anp32a, Acsl4, Evl, Sdc1, Arap3 and Cd52. Conclusions: Specific gene modules may provide better understanding of molecular mechanisms, and hub genes are potential candidates of therapeutic targets that may possible improve development of novel treatment approaches.

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Breakpoint Analysis of Transcriptional and Genomic Profiles Uncovers Novel Gene Fusions Spanning Multiple Human Cancer Types

Cited by 105 publications

References 92 publications

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

Palbociclib treatment of FLT3-ITD+ AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6

PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations

Identification of Specific Gene Modules in Mouse Lung Tissue Exposed to Cigarette Smoke

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