From breaking bad to worse: exploiting homologous DNA repair deficiency in cancer.

Abstract:

:DNA repair deficiencies are common among cancer cells and represent a potential vulnerability that might be exploited by targeting compensatory repair pathways. However, the identification of synthetically lethal combinations of DNA repair defects, although of significant clinical relevance, has been somewhat anecdotal. Although numerous models have been proposed to explain synthetic lethality among DNA repair mutations, we have only a limited understanding of why a given mutation should render cells sensitive to another. In this issue of Cancer Discovery, Dietlein and colleagues define a general connection between mutations in genes involved in homologous recombination and sensitivity to inhibitors of non-homologous end joining. In doing so, they provide a mechanism to demarcate a set of seemingly diverse tumors that may be highly responsive to established DNA repair-targeted therapeutics.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Hemann MT

doi

10.1158/2159-8290.CD-14-0316

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

516-8

issue

5

eissn

2159-8274

issn

2159-8290

pii

4/5/516

journal_volume

4

pub_type

  • Fasting May Complement Endocrine Therapy.

    abstract::Preliminary findings from a recent study suggest that combining intermittent fasting or a fasting-mimicking diet with endocrine therapy for hormone receptor-positive breast cancer may improve treatment efficacy and reduce side effects. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-084

    authors:

    更新日期:2020-11-01 00:00:00

  • Cancer cell metabolism: one hallmark, many faces.

    abstract::Cancer cells must rewire cellular metabolism to satisfy the demands of growth and proliferation. Although many of the metabolic alterations are largely similar to those in normal proliferating cells, they are aberrantly driven in cancer by a combination of genetic lesions and nongenetic factors such as the tumor micro...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-12-0345

    authors: Cantor JR,Sabatini DM

    更新日期:2012-10-01 00:00:00

  • 53BP1 regulates pRB via a lysine methylation-dependent interaction.

    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

    authors:

    更新日期:2014-09-01 00:00:00

  • Clonal evolution: multiregion sequencing of esophageal adenocarcinoma before and after chemotherapy.

    abstract::It is possible to decipher the clonal architecture of a tumor and the sequence in which cancer clones acquire genomic alterations through multiregion sequencing (M-seq). Serial evaluation of tumor specimens through M-seq can provide valuable information on the molecular basis of resistance to therapy. ...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-15-0739

    authors: Devarakonda S,Govindan R

    更新日期:2015-08-01 00:00:00

  • Unfurling the Genetic Map of Sarcomas.

    abstract::An international team of researchers has uncovered multiple new germline mutations that may influence the development of sarcomas. Notably, they found that variants in several DNA damage sensing and repair genes contribute greatly to sarcoma risk, including BRCA2, ATM, ATR, and ERCC2. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2016-108

    authors:

    更新日期:2016-10-01 00:00:00

  • Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia.

    abstract::Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% of poor prognosis acute myeloid leukaemias (AMLs). Limited clinical efficacy of FLT3 inhibitors highlights the need for alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD-dri...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-20-0738

    authors: Bjelosevic S,Gruber E,Newbold A,Shembrey C,Devlin JR,Hogg SJ,Kats L,Todorovski I,Fan Z,Abrehart TC,Pomilio G,Wei A,Gregory GP,Vervoort SJ,Brown KK,Johnstone RW

    更新日期:2021-01-12 00:00:00

  • Characteristics and Outcome of AKT1 E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry.

    abstract::AKT inhibitors have promising activity in AKT1E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinica...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-1209

    authors: Smyth LM,Zhou Q,Nguyen B,Yu C,Lepisto EM,Arnedos M,Hasset MJ,Lenoue-Newton ML,Blauvelt N,Dogan S,Micheel CM,Wathoo C,Horlings H,Hudecek J,Gross BE,Kundra R,Sweeney SM,Gao J,Schultz N,Zarski A,Gardos SM,Lee J,S

    更新日期:2020-04-01 00:00:00

  • Upping Enrollment of Veterans in Trials.

    abstract::The NCI and Department of Veterans Affairs (VA) are collaborating on the NCI and VA Interagency Group to Accelerate Trials Enrollment, or NAVIGATE, which will launch at 12 VA facilities across the country. The program aims to increase participation of veterans with cancer in NCI-sponsored clinical trials. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2018-097

    authors:

    更新日期:2018-08-01 00:00:00

  • Metabolic Codependencies in the Tumor Microenvironment.

    abstract::Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell intrinsic mechanisms activate signal transduction compon...

    journal_title:Cancer discovery

    pub_type: 杂志文章,评审

    doi:10.1158/2159-8290.CD-20-1211

    authors: Dey P,Kimmelman AC,DePinho RA

    更新日期:2021-01-27 00:00:00

  • Neoantigen Quality Predicts Immune Response, Survival.

    abstract::A new mathematical model finds that tumor neoantigen quality trumps quantity when it comes to predicting response to immunotherapy and the likelihood of long-term survival among patients with cancer. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-165

    authors:

    更新日期:2018-01-01 00:00:00

  • Panel OKs CAR T Therapy for Leukemia.

    abstract::An expert panel recommended approval of Novartis's experimental chimeric antigen T-cell therapy, tisagenlecleucel, for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia. The therapy would be the first of its kind approved for cancer and has the potential to transform standard of...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2017-108

    authors:

    更新日期:2017-09-01 00:00:00

  • IDO is a nodal pathogenic driver of lung cancer and metastasis development.

    abstract:UNLABELLED:Indoleamine 2,3-dioxygenase (IDO) enzyme inhibitors have entered clinical trials for cancer treatment based on preclinical studies, indicating that they can defeat immune escape and broadly enhance other therapeutic modalities. However, clear genetic evidence of the impact of IDO on tumorigenesis in physiolo...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-12-0014

    authors: Smith C,Chang MY,Parker KH,Beury DW,DuHadaway JB,Flick HE,Boulden J,Sutanto-Ward E,Soler AP,Laury-Kleintop LD,Mandik-Nayak L,Metz R,Ostrand-Rosenberg S,Prendergast GC,Muller AJ

    更新日期:2012-08-01 00:00:00

  • Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming.

    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

    authors: Hundeyin M,Kurz E,Mishra A,Rossi JAK,Liudahl SM,Leis KR,Mehrotra H,Kim M,Torres LE,Ogunsakin A,Link J,Sears RC,Sivagnanam S,Goecks J,Islam KMS,Dolgalev I,Savadkar S,Wang W,Aykut B,Leinwand J,Diskin B,Adam S,Is

    更新日期:2019-09-01 00:00:00

  • Tweaking Transcription to Stop AML Cell Growth.

    abstract::A new compound with anti-leukemia activity perturbs gene transcription by modulating super-enhancer activity. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2015-149

    authors:

    更新日期:2015-12-01 00:00:00

  • Proteomics Sharpens Brain Tumor Genomic Analysis.

    abstract::A recent study integrating proteomic and genomic analyses uncovered unexpected similarities in some types of pediatric brain tumors, such as certain craniopharyngiomas and low-grade gliomas, suggesting potential treatments and more refined prognoses. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2020-119

    authors:

    更新日期:2021-01-07 00:00:00

  • Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma.

    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 an...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-0367

    authors: 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 KP

    更新日期:2019-12-01 00:00:00

  • Checkpoint Kinase MEC1 (ATR) Structure Reveals Activation Mechanism.

    abstract::Mutating a conserved motif in the activation loop of MEC1 (ATR) revealed the activation mechanism. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2020-170

    authors:

    更新日期:2020-11-20 00:00:00

  • Second-generation ALK inhibitors: filling the non "MET" gap.

    abstract::Ceritinib and other second-generation inhibitors have demonstrated promising anticancer activity in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Specifically, they can overcome resistance due to certain gatekeeper mutations acquired following crizotinib exposure. These agents now provi...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-14-0410

    authors: Ramalingam SS,Khuri FR

    更新日期:2014-06-01 00:00:00

  • Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.

    abstract:UNLABELLED:Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0060

    authors: Smith CC,Zhang C,Lin KC,Lasater EA,Zhang Y,Massi E,Damon LE,Pendleton M,Bashir A,Sebra R,Perl A,Kasarskis A,Shellooe R,Tsang G,Carias H,Powell B,Burton EA,Matusow B,Zhang J,Spevak W,Ibrahim PN,Le MH,Hsu HH,H

    更新日期:2015-06-01 00:00:00

  • Two Worlds Collide: Unraveling the Role of the Immune System in BRAF-MEK Inhibitor Responses.

    abstract::Although BRAF-MEK inhibition can enhance the immune recognition of melanoma cells, the mechanisms that underlie this remain poorly defined. In this issue of Cancer Discovery, Erkes and colleagues present new data showing that BRAF-MEK inhibition activates pyroptosis in melanoma cells through gasdermin E cleavage, lead...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-19-1441

    authors: Smalley KSM

    更新日期:2020-02-01 00:00:00

  • Shades of T790M: Intratumor Heterogeneity in EGFR-Mutant Lung Cancer.

    abstract::In the setting of recent exciting clinical results and numerous ongoing trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant-specific EGFR inhibitor rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small-cell transformation are all clinically relevant mechan...

    journal_title:Cancer discovery

    pub_type: 评论,杂志文章

    doi:10.1158/2159-8290.CD-15-0616

    authors: Ichihara E,Lovly CM

    更新日期:2015-07-01 00:00:00

  • Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis.

    abstract::Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abunda...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-18-0567

    authors: Carrer A,Trefely S,Zhao S,Campbell SL,Norgard RJ,Schultz KC,Sidoli S,Parris JLD,Affronti HC,Sivanand S,Egolf S,Sela Y,Trizzino M,Gardini A,Garcia BA,Snyder NW,Stanger BZ,Wellen KE

    更新日期:2019-03-01 00:00:00

  • Immunotherapy toxic in obese mice.

    abstract::New research shows immunotherapy can cause lethal inflammation in both young and aged mice that are obese. Restricting calories in aged mice protected them from toxicity, and giving young obese mice a drug for autoimmune disease prevented the fatal reactions. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2014-171

    authors:

    更新日期:2015-01-01 00:00:00

  • Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors.

    abstract::HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant so...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-19-1014

    authors: Tsurutani J,Iwata H,Krop I,Jänne PA,Doi T,Takahashi S,Park H,Redfern C,Tamura K,Wise-Draper TM,Saito K,Sugihara M,Singh J,Jikoh T,Gallant G,Li BT

    更新日期:2020-05-01 00:00:00

  • Niraparib Slows Ovarian Cancer Progression.

    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

    authors:

    更新日期:2016-12-01 00:00:00

  • Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer.

    abstract::Despite recent advances in the use of immunotherapy, only a minority of patients with small cell lung cancer (SCLC) respond to immune checkpoint blockade (ICB). Here, we show that targeting the DNA damage response (DDR) proteins PARP and checkpoint kinase 1 (CHK1) significantly increased protein and surface expression...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-18-1020

    authors: Sen T,Rodriguez BL,Chen L,Corte CMD,Morikawa N,Fujimoto J,Cristea S,Nguyen T,Diao L,Li L,Fan Y,Yang Y,Wang J,Glisson BS,Wistuba II,Sage J,Heymach JV,Gibbons DL,Byers LA

    更新日期:2019-05-01 00:00:00

  • Durable Responses with Brentuximab Vedotin in cHL.

    abstract::According to survival results from a phase II trial of brentuximab vedotin, 34 patients with relapsed or refractory classic Hodgkin lymphoma had a complete response with this CD30-targeting antibody-drug conjugate; 13 remain in remission 5 years later. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-NB2016-100

    authors:

    更新日期:2016-09-01 00:00:00

  • LKB1 Inactivation Promotes ROS-Induced Plasticity in NSCLC.

    abstract::LKB1 inactivation generates a redox imbalance that promotes ADC-to-SCC transdifferentiation in NSCLC. ...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-RW2015-089

    authors:

    更新日期:2015-07-01 00:00:00

  • Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.

    abstract:UNLABELLED:CD96 has recently been shown as a negative regulator of mouse natural killer (NK)-cell activity, with Cd96(-/-)mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different...

    journal_title:Cancer discovery

    pub_type: 杂志文章

    doi:10.1158/2159-8290.CD-15-0944

    authors: Blake SJ,Stannard K,Liu J,Allen S,Yong MC,Mittal D,Aguilera AR,Miles JJ,Lutzky VP,de Andrade LF,Martinet L,Colonna M,Takeda K,Kühnel F,Gurlevik E,Bernhardt G,Teng MW,Smyth MJ

    更新日期:2016-04-01 00:00:00

  • XPO1 Inhibitor Approved for Multiple Myeloma.

    abstract::The FDA granted accelerated approval to selinexor plus low-dose dexamethasone for triple-class refractory multiple myeloma, despite an advisory panel's concerns about the drug's toxicity and the lack of randomized clinical data. ...

    journal_title:Cancer discovery

    pub_type: 新闻

    doi:10.1158/2159-8290.CD-NB2019-085

    authors:

    更新日期:2019-09-01 00:00:00