Abstract:
:Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confirmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefit and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identified in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fisogatinib, which were confirmed to mediate resistance in vitro and in vivo. A gatekeeper-agnostic, pan-FGFR inhibitor decreased HCC xenograft growth in the presence of these mutations, demonstrating continued FGF19-FGFR4 pathway dependence. These results validate FGFR4 as an oncogenic driver and warrant further therapeutic targeting of this kinase in the clinic. SIGNIFICANCE: Our study is the first to demonstrate on-target FGFR4 kinase domain mutations as a mechanism of acquired clinical resistance to targeted therapy. This further establishes FGF19-FGFR4 pathway activation as an oncogenic driver. These findings support further investigation of fisogatinib in HCC and inform the profile of potential next-generation inhibitors.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Hatlen MA,Schmidt-Kittler O,Sherwin CA,Rozsahegyi E,Rubin N,Sheets MP,Kim JL,Miduturu C,Bifulco N,Brooijmans N,Shi H,Guzi T,Boral A,Lengauer C,Dorsch M,Kim RD,Kang YK,Wolf BB,Hoeflich KPdoi
10.1158/2159-8290.CD-19-0367subject
Has Abstractpub_date
2019-12-01 00:00:00pages
1686-1695issue
12eissn
2159-8274issn
2159-8290pii
2159-8290.CD-19-0367journal_volume
9pub_type
杂志文章相关文献
Cancer Discovery文献大全abstract::The FDA approved atezolizumab to treat advanced bladder cancer when cisplatin chemotherapy is contraindicated. The approval offers a potentially more effective alternative to carboplatin-based chemotherapy for frail, elderly patients. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-064
更新日期:2017-06-01 00:00:00
abstract::In the large international phase III MAVORIC trial, patients with previously treated cutaneous T-cell lymphoma who received the anti-CCR4 monoclonal antibody mogamulizumab experienced significantly longer progression-free survival and higher response rates, as well as better quality of life, than those who received vo...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2018-001
更新日期:2018-02-01 00:00:00
abstract::YY1 preferentially occupies active enhancers and promoters and forms dimers to promote DNA looping. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2017-233
更新日期:2018-02-01 00:00:00
abstract::LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2018-010
更新日期:2018-03-01 00:00:00
abstract::Somatic ERBB3 hot-spot mutations promote oncogenic signaling in a subset of human tumors. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2013-107
更新日期:2013-07-01 00:00:00
abstract::Researchers identified a small molecule that stimulates the production of stem cells in umbilical cord blood, potentially expanding treatment options for adults with hematologic cancers. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2014-153
更新日期:2014-12-01 00:00:00
abstract::The NIH has approved the framework to build a national research cohort of 1 million Americans, a key part of President Obama's Precision Medicine Initiative. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-146
更新日期:2015-12-01 00:00:00
abstract:UNLABELLED:Colorectal cancer was one of the first solid tumors to be classified on the basis of molecular profiling. Microsatellite instability has allowed researchers to distinguish a specific subtype of colorectal cancer that has a clearly identified molecular origin (mismatch repair deficiency), arises on a heredita...
journal_title:Cancer discovery
pub_type: 杂志文章,评审
doi:10.1158/2159-8290.CD-12-0471
更新日期:2013-05-01 00:00:00
abstract::mTOR inhibition with the ATP-competitive kinase inhibitor AZD8055 induces receptor tyrosine kinase-dependent feedback activation of AKT. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-11-0157
更新日期:2011-08-01 00:00:00
abstract::Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer. Improved progression-free survival was seen regardless of the presence or absence of germline BRCA mutations, or o...
journal_title:Cancer discovery
pub_type:
doi:10.1158/2159-8290.CD-NB2016-137
更新日期:2016-12-01 00:00:00
abstract::Researchers have used mass spectrometry to conduct proteomic analyses of 77 genomically characterized breast tumors. Through this approach, they've uncovered functional consequences of somatic mutations. For instance, EGFR overexpression in basal-like breast cancer is potentially driven by the loss of two genes, SKP1 ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2016-078
更新日期:2016-08-01 00:00:00
abstract::An intact gut microbiome was needed to protect genetically vulnerable mice from developing leukemia. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-139
更新日期:2020-11-01 00:00:00
abstract:SUMMARY:In this issue of Cancer Discovery, Romero and colleagues identify somatic mutations and deletions of MAX, and also define what seem to be mutually exclusive alterations in MYC family members and other MYC-associated factors in small cell lung cancer. Taken together, these data highlight the importance of MYC si...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-14-0069
更新日期:2014-03-01 00:00:00
abstract::MHC-I and MHC-II regulators in lymphomas, some of which had subtype or tumor specificity, were identified. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2020-178
更新日期:2020-12-11 00:00:00
abstract::Asparagine promotes the survival of cancer cells in response to glutamine withdrawal. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-RW2014-205
更新日期:2014-11-01 00:00:00
abstract::Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4-CD8-NK1.1- innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and human...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-19-0161
更新日期:2019-09-01 00:00:00
abstract:UNLABELLED:Knowledge of "actionable" somatic genomic alterations present in each tumor (e.g., point mutations, small insertions/deletions, and copy-number alterations that direct therapeutic options) should facilitate individualized approaches to cancer treatment. However, clinical implementation of systematic genomic ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-11-0184
更新日期:2012-01-01 00:00:00
abstract::In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-20-0263
更新日期:2020-11-11 00:00:00
abstract::Adding a PI3K inhibitor to anti-estrogen receptor therapy may be a viable treatment option for women with advanced hormone receptor-positive breast cancer that becomes resistant to endocrine therapy, according to findings from the phase III BELLE-2 trial, presented at the 2015 San Antonio Breast Cancer Symposium. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2015-176
更新日期:2016-02-01 00:00:00
abstract::The Genomics of Drug Sensitivity in Cancer project recently added 4 years of additional data to a large-scale database designed to identify predictive biomarkers for cancer therapies. Freely available online, these data are driving research on the relationship between genomic features and drug responses to better tail...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2019-114
更新日期:2019-11-01 00:00:00
abstract:: BRAF fusions and mutations are the most frequent genetic alterations in pediatric low-grade gliomas. The work from Wang and colleagues identifies an acquired secondary BRAF mutation that confers resistance to pharmacologic BRAF inhibition in a BRAFV600E glioma. The authors demonstrate that the mu...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-18-0784
更新日期:2018-09-01 00:00:00
abstract::Celgene acquired Juno Therapeutics for $9 billion and is spending up to $7 billion on Impact Biomedicines in an effort to diversify its hematology portfolio with chimeric antigen receptor T-cell therapies and a JAK2 inhibitor before its best seller, lenalidomide, faces competition from generics. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2018-007
更新日期:2018-03-01 00:00:00
abstract::An increasing number of anticancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Recent evidence suggests that the selection of patients whose tumors harbor specific genetic alterations identifies the subset of patients who are most likely to benefit from the use ...
journal_title:Cancer discovery
pub_type: 杂志文章,评审
doi:10.1158/2159-8290.CD-11-0110
更新日期:2011-09-01 00:00:00
abstract::Based on results of the phase III BILCAP study, adjuvant capecitabine should become standard treatment for patients with biliary tract cancer. Among 430 patients who were treated according to the study protocol, capecitabine was associated with a 25% lower risk of death than observation. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2017-079
更新日期:2017-07-01 00:00:00
abstract::By law, the U.S. Food and Drug Administration has the authority, through its Center for Tobacco Products, to regulate the manufacture, marketing, and distribution of tobacco products. Its director, Mitchell Zeller, JD, talks about how the center, though its research, public education, and enforcement activities, aims ...
journal_title:Cancer discovery
pub_type: 面试
doi:10.1158/2159-8290.CD-ND2013-028
更新日期:2014-01-01 00:00:00
abstract:UNLABELLED:Genetic approaches have shown that the p110β isoform of class Ia phosphatidylinositol-3-kinase (PI3K) is essential for the growth of PTEN-null tumors. Thus, it is desirable to develop p110β-specific inhibitors for cancer therapy. Using a panel of PI3K isoform-specific cellular assays, we screened a collectio...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-12-0003
更新日期:2012-05-01 00:00:00
abstract::Amid concerns over the spread of COVID-19, oncology practices have "gone virtual," with video appointments scheduled for any service that does not require diagnostic testing or treatment. ...
journal_title:Cancer discovery
pub_type: 杂志文章
doi:10.1158/2159-8290.CD-NB2020-027
更新日期:2020-06-01 00:00:00
abstract::Circadian rhythms integrate many physiological pathways, helping organisms to align the timing of various internal processes to daily cycles in the external environment. Disrupted circadian rhythmicity is a prominent feature of modern society, and has been designated as a probable carcinogen. Here, we review multiple ...
journal_title:Cancer discovery
pub_type: 杂志文章,评审
doi:10.1158/2159-8290.CD-20-0413
更新日期:2020-10-01 00:00:00
abstract::53BP1 integrates pRB activity with the DNA damage response by binding to methylated K810. ...
journal_title:Cancer discovery
pub_type: 评论,杂志文章
doi:10.1158/2159-8290.CD-RW2014-164
更新日期:2014-09-01 00:00:00
abstract::A new study of zebrafish may explain why only certain skin cells grow into tumors. Besides melanoma-promoting mutations, these cells express key neural crest genes, such as crestin and sox10, that induce regression to an embryonic state. They also bear epigenetic changes that might amplify expression of these genes. ...
journal_title:Cancer discovery
pub_type: 新闻
doi:10.1158/2159-8290.CD-NB2016-019
更新日期:2016-04-01 00:00:00