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In This Issue IN THIS ISSUE AACR Project GENIE Facilitates Sharing of Genomic and Clinical Data • Project GENIE launched with data • Project GENIE aims to promote • Data from Project GENIE may guide from 19,000 patients from 8 institu­ data sharing to enhance precision identification of drug targets and tions with a variety of tumor types . medicine research . biomarkers in patients with cancer . Genomic profi ling of tumors accessible in the cBioPortal for Cancer Genomics. Despite the has become increasingly com- differences in genomic testing at the contributing centers, the mon across cancer types, but genomic data collected so far are largely concordant across the data are not regularly made the centers, and mutation rates are similar to those reported by available to the entire research The Cancer Genome Atlas. Initial results from Project GENIE community. The American Asso- suggest that more than 30% of tumors harbor potentially ciation for Cancer Research clinically actionable mutations. Advantages of this platform (AACR) launched the Genomics, include integration of clinical data from electronic health Evidence, Neoplasia, Informa- records and increased statistical power to potentially facilitate tion, Exchange (GENIE) project understanding of the clinical relevance of somatic mutations in partnership with eight academic institutions to facilitate and improve patient selection for targeted therapies. The large-scale sharing of genomic and clinical data. The AACR establishment of infrastructure for integrating genomic and Project GENIE Consortium released the fi rst of set of data clinical data has the potential to aid identifi cation of thera- from 19,000 patients in January 2017, and the number of sam- peutic targets and biomarkers of treatment and response in ples included is expected to grow to more than 100,000 within patients with cancer to enhance precision medicine research 5 years as more centers join the Consortium. Data from par- and improve patient outcomes. n ticipating centers include matched clinical and genomic data from a variety of tumor types that are harmonized and made See article, p. 818. TBK1/IKKd Is a Potential Target in MAPk Inhibitor–Resistant Melanoma • A SOX10­associated 5­gene bio­ • SOX10­independent, BRAF/MEK • TBK1/IKKε addiction defines an marker discriminates MAPK inhibitor– inhibitor–resistant melanoma is innate immune subtype with YAP sensitive and –resistant melanomas . sensitive to TBK1/IKKε inhibitors . activation and epigenetic remodeling . The effi cacy of BRAF/MEK the noncanonical IκB kinases TANK-binding kinase 1 (TBK1) inhibitors in BRAF-mutant mela- and IKKε (encoded by IKBKE), independent of BRAF status. noma is limited by the emergence TBK1/IKKε–sensitive melanomas were enriched for innate of resistance, which often occurs immune signaling and exhibited TBK1/IKKε–mediated acti- via mechanisms that reactivate vation of YAP and AKT survival signaling, which may underlie MAPK signaling. To characterize the dependency of this subtype on TBK1/IKKε. In addition, potential alternative therapeutic TBK1/IKKε–sensitive melanomas were characterized by targets in BRAF/MEK inhibitor– increased expression of nicotinamide N-methyltransferase, resistant melanoma, Eskiocak which has been implicated in epigenetic remodeling and and colleagues performed an chromatin relaxation. Consistent with this fi nding, global integrative analysis of a functional genomic screen and copy- H3K27 trimethylation was reduced in TBK1/IKKε–sensitive number variation in melanoma cell lines and tumors. Among cells, and inhibition of the H3K27 methyltransferase EZH2 the identifi ed melanoma cell survival genes, addiction to was suffi cient to confer sensitivity to TBK1/IKKε inhibitors SOX10, assessed by expression of a 5-gene biomarker, dis- in previously resistant cells. Together, these fi ndings defi ne tinguished two mechanistic subtypes of melanoma: SOX10- potential molecular predictors of response to BRAF/MEK dependent, BRAF-mutant melanomas sensitive to BRAF/ inhibition and identify TBK1/IKKε as a candidate therapeu- MEK inhibitors and SOX10-independent, BRAF/MEK inhib- tic target for BRAF/MEK inhibitor–resistant melanoma. n itor–resistant melanomas. Targeted therapy–resistant mela- nomas were found to be selectively sensitive to inhibition of See article, p. 832. AUGUST 2017 CANCER DISCOVERY | 783 Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. 00-CD-16-FM_Aug.indd 783 7/20/17 10:07 AM IN THIS ISSUE HDAC and BET Inhibitors Synergize to Promote Antitumor Immune Responses • The HDAC6 inhibitor ricolinostat in • Ricolinostat promotes T­cell activ­ • Dual HDAC6/BET targeting may poten­ combination with the BET inhibitor ity and JQ1 reduces Treg activity to tially enhance the antitumor immune JQ1 promotes T­cell function . suppress tumor growth . response in patients with NSCLC . Epigenetic drugs including ther, ricolinostat increased surface expression of MHC class histone deacetylase (HDAC) II molecules and CD86 on monocytes and tumor-associated inhibitors and bromodomain macrophages, suggesting that ricolinostat promotes pheno- and extraterminal domain (BET) typic changes that support improved antigen presentation and inhibitors have shown prom- costimulatory capabilities. These changes were recapitulated in ise in a variety of tumor types. vivo in a mouse model of NSCLC, where ricolinostat treatment Although immunomodulatory promoted a more mature tumor-infi ltrating macrophage phe- effects have been reported, the notype and increased tumor T-cell activation. The BET inhibi- effects of HDAC and BET inhibi- tor JQ1 acted on Treg cells within tumors, disrupting their tors on the tumor immune gene expression patterns and diminishing their suppressive microenvironment have not been fully elucidated, prompt- activity. Dual inhibition with ricolinostat and JQ1 enhanced ing Adeegbe and colleagues to investigate the immunoregula- the antitumor activity of tumor-infi ltrating T cells, suppressed tory properties of these drugs in non–small cell lung cancer tumor growth, and extended survival in mice with NSCLC. (NSCLC). In peripheral blood mononuclear cells (PBMC) and Collectively, these fi ndings uncover immunoregulatory effects tumors from patients with NSCLC, the selective HDAC6 of HDAC and BET inhibition, and suggest that dual targeting inhibitor ricolinostat reduced the proportion of suppressive may enhance the antitumor immune response in NSCLC. n CD4+FOXP3+ regulatory T cells (Treg) and increased expres- sion of CD69 on T cells, suggesting T-cell activation. Fur- See article, p. 852. Comprehensive Methylation Profiling Reveals Epigenetic Subtypes in AML • Differential methylation of nonpro­ • Comprehensive methylome sequenc­ • Co­mutation of IDH2 and DNMT3A moter regulatory elements defines ing is superior to promoter­specific results in epigenetic antagonism the epigenetic subtype in AML . analysis for capturing AML biology . that may sensitize to MEK inhibitors . The effects of disrupted DNA cytosine methylation. AML with dominant hypermethyla- methylation patterns in regions tion was associated with epigenetic disruption of promoters. outside of promoters and CpG Conversely, AML with dominant hypomethylation exhibited islands are not well understood greater disruption of distal and intronic regions. Co-muta- in acute myeloid leukemia tion of IDH2 and DNMT3A, which have opposing effects on (AML). Glass and colleagues per- DNA methylation, resulted in an epigenetic antagonism, and formed enhanced reduced rep- this subset of AML had the least differential methylation. In resentation bisulfi te sequencing preleukemic hematopoietic stem cells, induction of Dnmt3A (ERRBS) on a panel of 119 pri- and Idh2 mutations promoted epigenetic antagonism prior to mary AMLs to evaluate cytosine malignant transformation, indicating it is not a consequence methylation changes in nonpromoter gene regulatory ele- of transformation. Transcriptome analysis in patients with ments. This comprehensive methylome sequencing approach IDH2/DNMT3A-mutant AML revealed upregulation of the more precisely linked genetic lesions to disrupted cytosine RAS signaling signature; accordingly, double-mutant cells methylation patterns than promoter-specifi c methylation. exhibited sensitivity to MEK inhibition in ex vivo experiments. CpG methylation in “gene neighborhoods” between 2kb Altogether, this comprehensive DNA methylation profi ling and 50kb from the transcription start or end site was best analysis shows that differential methylation of nonpromoter able to capture the epigenetic patterning observed in AML. regulatory elements drives AML epigenetic identity. n Active enhancers displayed strong focal changes in meth- ylation whereas promoters exhibited less robust changes in See article, p. 868. 784 | CANCER DISCOVERY AUGUST 2017 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 26, 2021. © 2017 American Association for Cancer Research. 00-CD-16-FM_Aug.indd 784 7/20/17 10:07 AM IN THIS ISSUE PAX3–FOXO1-Positive Rhabdomyosarcomas Are Dependent on BRD4 • PAX3–FOXO1 promotes chromatin • PAX3–FOXO1 interacts with MYOD, • BET inhibitors may potentially be remodeling to establish myogenic su­ MYOG, and MYCN, and recruits beneficial in patients with fusion­ perenhancers in rhabdomyosarcoma . BRD4 to superenhancers . positive rhabdomyosarcoma . Alveolar rhabdomyosarcoma genes. Superenhancer analysis revealed a distinct landscape is a myogenic cancer driven
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