PARP Inhibitors Cancer Review
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A phase II study of nab-paclitaxel in combination with ramucirumab in patients with previously treated advanced gastric cancer

Nanoparticle albumin-bound (nab)-paclitaxel was developed to improve paclitaxel solubility
and does not need premedication to avoid infusion-related reactions associated with
solvent-based (sb)-paclitaxel. We conducted a phase II trial to investigate the efficacy
and safety of nab-paclitaxel plus ramucirumab combination therapy for previously treated
advanced gastric cancer.
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PARP Inhibitors Cancer Review
Poly ADP ribose polymerase (PARP) inhibitors for triple negative breast cancer (TNBC) The Phase III failure of Iniparib to extend OS or PFS in TNBC patients has cast a dark shadow on PARP inhibitors drug class and R&D in one of the most active area in industrial oncology. The most advanced product iniparib (BSI 201, Sanofi Aventis) has shown 30% response rates in Phase I trials and 62% in triple negative breast cancer patients in Phase II trials. Addition of Iniparib to chemotherapy increased overall survival to 12.2 months from 7.7 months on gemcitabine+ carboplatin. A global Phase III trial in squamous NSCLC was initiated in 2010. It has completed enrollment of TNBC patients in Phase III trials. The NDA and MAA is expected to be filed in 1-2 Q 2011. The second product olaparib has shown 40% response rates in extended Phase I trials and completed Phase II studies. Olaparib planned Phase III trials in BRCA1/BRCA2 positive breast cancer was cancelled by Astra Zeneca and focus shifted to Phase III in ovarian cancer patients. Olaparib extended PFS and time to progression by 4 and 4.6 months over placebo. Veliparib from Abbott is the third PARPi to complete Phase II trials in advanced metastatic breast cancer with 37% RR in BRCA positive patients. Tumor cells use PARP pathway to repair DNA damage to proliferate and replicate. A new test to identify defective genes RAD51 assay indicates that PARP inhibitors may benefit 60% of the ovarian cancer patients. Inhibition of PARP offers novel agents for treating tumors with DNA repair defects. PARP inhibitors have the market potential to generate 10-15 billion annual sales with each brand worth $3-5 billion in sales within 5 years after approval and marketing in major markets.
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Wendt Lab Metastatic Breast cancer

Wendt Lab Metastatic Breast cancer | PARP Inhibitors Cancer Review | Scoop.it
Metastatic breast cancer research. Bioluminesent imaging of drug resistant cancer. Wendt lab at the Purdue center for cancer research.Mouse models of breast cancer progression...
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Impact of Circulating Tumor DNA (ctDNA) in Patients with Gastrointestinal Malignancies | Frontiers Research Topic

Impact of Circulating Tumor DNA (ctDNA) in Patients with Gastrointestinal Malignancies | Frontiers Research Topic | PARP Inhibitors Cancer Review | Scoop.it
Circulating tumor DNA (ctDNA) testing is rapidly emerging as a new tool for scientists and oncologists treating gastrointestinal cancers. The varied numbers of testing platforms, either research or the ones that are commercially available, are helping us understand several fundamental aspects of...
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Revolution Medicines Phosphatase Platform for new cancer drugs

Revolution Medicines Phosphatase Platform for new cancer drugs | PARP Inhibitors Cancer Review | Scoop.it
Revolution Medicines has made a major commitment toward discovering and developing small molecule inhibitors of protein tyrosine phosphatases (PTPs).
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Cancers | Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations ...

Cancers | Rare Stochastic Expression of O6-Methylguanine- DNA Methyltransferase (MGMT) in MGMT-Negative Melanoma Cells Determines Immediate Emergence of Drug-Resistant Populations ... | PARP Inhibitors Cancer Review | Scoop.it
The chemotherapeutic agent temozolomide (TMZ) kills tumor cells preferentially via alkylation of the O6-position of guanine. However, cells that express the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), or harbor deficient DNA mismatch repair (MMR) function, are profoundly...
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FDA approves 4th PARP inhibitor Pfizer TALZENNA®( talazoparib) for gBRCAm HER2-negative locally advanced or metastatic breast cancer

FDA approves 4th PARP inhibitor Pfizer TALZENNA®( talazoparib) for gBRCAm HER2-negative locally advanced or metastatic breast cancer | PARP Inhibitors Cancer Review | Scoop.it

On October 16, 2018, the Food and Drug Administration approved talazoparib (TALZENNA, Pfizer Inc.), a poly (ADP-ribose) polymerase (PARP) inhibitor, for patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2‑negative locally advanced or metastatic breast cancer. Patients must be selected for therapy based on an FDA-approved companion diagnostic for talazoparib.

Approval was based on EMBRACA (NCT01945775), an open‑label trial randomizing 431 patients (2:1) with gBRCAm HER2‑negative locally advanced or metastatic breast cancer to receive talazoparib (1 mg) or physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). All patients were required to have a known deleterious or suspected deleterious gBRCA mutation and must have received no more than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease. Patients were required to have received treatment with an anthracycline and/or a taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting.

The primary efficacy outcome was progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by blinded independent central review. Estimated median PFS was 8.6 and 5.6 months in the talazoparib and chemotherapy arms, respectively (HR 0.54; 95% CI: 0.41, 0.71; p<0.0001).

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity. Most common (≥20%) adverse reactions of any grade were fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite.

FDA also approved the BRACAnalysis CDx test (Myriad Genetic Laboratories, Inc.) to identify patients with breast cancer with deleterious or suspected deleterious gBRCAm who are eligible for talazoparib. The effectiveness of the BRACAnalysis CDx test was based on the EMBRACA trial population for whom deleterious or suspected deleterious gBRCAm status was confirmed with either prospective or retrospective testing with BRACAnalysis CDx.

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Human breast tumor-infiltrating CD8 + T cells retain polyfunctionality despite PD-1 expression

Human breast tumor-infiltrating CD8 + T cells retain polyfunctionality despite PD-1 expression | PARP Inhibitors Cancer Review | Scoop.it
Expression of the checkpoint molecule programmed cell death protein 1 (PD-1) is considered a marker of T cells exhaustion. Here the authors show that CD8T cells isolated from breast cancer patients are perfectly functional despite PD-1 expression while those isolated from melanoma patients are not.
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Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data

Treatment of brain metastases with stereotactic radiosurgery and immune checkpoint inhibitors: An international meta-analysis of individual patient data | PARP Inhibitors Cancer Review | Scoop.it
Brain metastases are the most common intracranial tumor seen in adults and may be
seen up to 10 times more frequently than primary brain tumors [1]. Up to 30% of adults with cancer and more than 200,000 patients are affected by brain metastases annually in the United States [2], primarily from...
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MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells

MYBL2 Supports DNA Double Strand Break Repair in Hematopoietic Stem Cells | PARP Inhibitors Cancer Review | Scoop.it
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Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases characterized by blood cytopenias that occur as a result of somatic mutations in hematopoietic stem cells (HSC).
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Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2) | PARP Inhibitors Cancer Review | Scoop.it
Breast cancers with amplification or mutation in the epidermal growth factor receptor (EGFR) family member HER2 are usually treated with targeted inhibitors, but resistance is common. Amplification and mutation of HER2 are generally considered mutually exclusive occurrences in treatment-naïve patients. However, Cocco et al . discovered a small proportion of treatment-naïve and, more often, previously treated patients with metastatic breast cancer in which HER2 amplification and mutation were coincident. It is not yet clear why, but these co-amplified/mutant cells were resistant to currently approved HER2-specific and HER2/EGFR-specific inhibitors but were sensitive to the new pan-EGFR inhibitor neratinib. Neratinib, which inhibits EGFR and HER2, as well as HER3 and HER4, was more effective at blocking the activity of the EGFR pathway and other receptor tyrosine kinases, common modes of resistance in HER2-driven tumors. Patients and mice bearing their tumor cells showed improved survival and even tumor regression on neratinib, suggesting that this may be a treatment option for certain breast cancer patients.

Mutations in ERBB2 , the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” ( ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2 /HER2.
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IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity | PARP Inhibitors Cancer Review | Scoop.it
In human and mouse models of ovarian cancer, endoplasmic reticulum stress and the activation of the IRE1α–XBP1 pathway decreases the metabolic fitness of T cells and limits their anti-tumour functions.
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Resistance to therapy and tumor relapse attributed to specific cancer cell population

Resistance to therapy and tumor relapse attributed to specific cancer cell population | PARP Inhibitors Cancer Review | Scoop.it
Resistance to therapy is a major problem in cancer patients, as resistant cells are at the root of tumour relapse and are associated with high morbidity and mortality. A better understanding of the mechanisms associated with ...
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A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy

A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy | PARP Inhibitors Cancer Review | Scoop.it
Treatment of basal cell carcinoma with Smoothened inhibitors leaves a small population of quiescent cells that can drive relapse but can be eliminated by additional treatment with a Wnt signalling inhibitor.
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Checkpoint blockade therapy resistance in Hodgkin's lymphoma

CORRESPONDENCE| VOLUME 392, ISSUE 10154, P1194-1196, OCTOBER 06, 2018 Checkpoint blockade therapy resistance in Hodgkin's lymphoma Published:October 06, 2018DOI:https://doi.org/10.1016/S0140-6736(18)31867-1 About 50 years ago, the enigma of Hodgkin's lymphoma was depicted as the Hodgkin maze in two editorials in The Lancet.1,  2 The uncertainties of the time were expressed through two questions: “Infection or neoplasm?” and “One entity or two (or more)?”.2 Subsequently, advances in cell biology and molecular pathology provided answers to these questions. Substantial evidence now indicates that classical Hodgkin's lymphoma is a distinct neoplastic entity, with heterogeneous pathological features, which might be associated with Epstein-Barr virus infection. Cases with intermediate features between classical Hodgkin's lymphoma and diffuse large B-cell lymphomas have been recognised. Typically, rare Hodgkin and Reed-Sternberg (HRS) cells are surrounded by immune and inflammatory cells, including T helper 2 cells and T regulatory cells.3 HRS cells express programmed cell death ligand (PD-L) 1 and 2, which bind programmed cell death 1 (PD-1), a receptor expressed by T cells (figure). Binding activates the PD-1 signal transduction pathway, which inactivates tumour-specific T cells. The PD-L1–PD-1 pathway, therefore, functions as a checkpoint that regulates T cell-mediated immune responses. Through this mechanism, HRS cells escape immune surveillance and thereby evade immune destruction. Checkpoint-inhibiting antibodies showed promising results in the treatment of relapsed or chemotherapy-refractive classical Hodgkin's lymphoma, with durable clinical responses in heavily pretreated patients, although their tumours developed immune resistance.3 The mechanisms of resistance to checkpoint-inhibiting antibodies have been partially identified in solid tumours,4 but remain largely unknown in classical Hodgkin's lymphoma. These uncertainties mean that we are again in the Hodgkin maze, because of the disease's enigmatic tangle that includes inflammatory responses to HRS cells and Epstein-Barr virus, the aberrant phenotype of HRS cells, deregulated oncogenic pathways, immune escape, and tumor–host interface crosstalk (figure). We can learn about the mechanisms of resistance to checkpoint blockade in classical Hodgkin's lymphoma from progress in solid tumours. For example, a preclinical study showed that resistance correlated with infiltration of the tumour by immunosuppressive myeloid cells.4 Therefore, to understand resistance to checkpoint blockade in classical Hodgkin's lymphoma, we should study the inflammatory and immune cells in the tumour microenvironment and the immunomodulatory proteins these cells express. This research is now possible using multiplexing immunofluorescence and immunohistochemistry, and digital image analysis.5 Such research should reveal how to overcome drug resistance in classical Hodgkin's lymphoma through rational combinations of checkpoint inhibitors and cellular immunotherapy. We thank Valerie Matarese for precious collaboration and editing of the manuscript. We declare no competing interests. References The Lancet The Hodgkin maze. Lancet. 1969; 294: 728-730 The Lancet Further in the Hodgkin maze. Lancet. 1971; 297: 1053-1054 Carbone A Gloghini A Castagna L Santoro A Carlo-Stella C Primary refractory and early-relapsed Hodgkin's lymphoma: strategies for therapeutic targeting based on the tumour microenvironment. J Pathol. 2015; 237: 4-13 View in Article De Henau O Rausch M Winkler D et al. Overcoming resistance to checkpoint blockade therapy by targeting PI3Kγ in myeloid cells. Nature. 2016; 539: 443-447 View in Article Carey CD Gusenleitner D Lipschitz M et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood. 2017; 130: 2420-2430 View in Article Article Info Publication History Published: 06 October 2018 IDENTIFICATION DOI: 10.1016/S0140-6736(18)31867-1 Copyright © 2018 Elsevier Ltd. All rights reserved. ScienceDirect Access this article on ScienceDirect
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Evolution of Metastases in Space and Time under Immune Selection

Highlights

Different escape mechanisms delineated by lack of adaptive immunity or immunoediting

Non-recurrent clones are immunoedited; progressing clones are immune privileged

Immunoediting and Immunoscore are predictive factors of metastasis recurrence

Parallel selection model describes clonal immunoediting and tumor evolution
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Photosensitiser functionalised luminescent upconverting nanoparticles for efficient photodynamic therapy of breast cancer cells - Photochemical & Photobiological Sciences (RSC Publishing)

Photosensitiser functionalised luminescent upconverting nanoparticles for efficient photodynamic therapy of breast cancer cells - Photochemical & Photobiological Sciences (RSC Publishing) | PARP Inhibitors Cancer Review | Scoop.it
Photodynamic therapy (PDT) is a well-established treatment of cancer in which cell toxic reactive oxygen species, including singlet oxygen (1O2), are produced by a photosensitiser drug following irradiation of a specific wavelength.
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Researchers Explore a Cancer Paradox - The New York Times

Researchers Explore a Cancer Paradox - The New York Times | PARP Inhibitors Cancer Review | Scoop.it
Healthy cells carry a surprising number of cancer-linked mutations, but they don’t turn into tumors. What’s holding them back?
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Machine-learning driven findings uncover new cellular players in tumor microenvironment | EurekAlert! Science News

Machine-learning driven findings uncover new cellular players in tumor microenvironment | EurekAlert! Science News | PARP Inhibitors Cancer Review | Scoop.it
New findings presented today by CytoReason reveals possible new cellular players in the tumor microenvironment that could impact the treatment process for the most in-need patients -- those who have already failed to respond to ipilimumab (anti-CTLA4) immunotherapy.
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NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy | PARP Inhibitors Cancer Review | Scoop.it
Journal of Cancer Metastasis and Treatment is an open access journal, focusing on basic and clinical studies related to cancer cell, cell biology, oncology, radiation therapy and radiology, obstetrics and gynecology, pediatrics, surgery, hematology, neuro-oncology, etc.
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Do you know that Cancer stem cells use normal genes in abnormal ways

Do you know that Cancer stem cells use normal genes in abnormal ways | PARP Inhibitors Cancer Review | Scoop.it
Cancer stem cells use normal genes in abnormal ways CDK1 is a "normal" protein - its presence drives cells through the cycle of replication.And MHC Class I...
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Loss of E-cadherin Enhances IGF1–IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors

Loss of E-cadherin Enhances IGF1–IGF1R Pathway Activation and Sensitizes Breast Cancers to Anti-IGF1R/InsR Inhibitors | PARP Inhibitors Cancer Review | Scoop.it
Purpose: Insulin-like growth factor 1 (IGF1) signaling regulates breast cancer initiation and progression and associated cancer phenotypes. We previously identified E-cadherin ( CDH1 ) as a repressor of IGF1 signaling and in this study examined how loss of E-cadherin affects IGF1R signaling and...
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Classification and Personalized Prognosis in Myeloproliferative Neoplasms | NEJM

Classification and Personalized Prognosis in Myeloproliferative Neoplasms | NEJM | PARP Inhibitors Cancer Review | Scoop.it
Abstract
BACKGROUND
Myeloproliferative neoplasms, such as polycythemia vera, essential thrombocythemia, and myelofibrosis, are chronic hematologic cancers with varied progression rates. The genomic characterization of patients with myeloproliferative neoplasms offers the potential for personalized diagnosis, risk stratification, and treatment.

METHODS
We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms, comprehensively annotating driver mutations and copy-number changes. We developed a genomic classification for myeloproliferative neoplasms and multistage prognostic models for predicting outcomes in individual patients. Classification and prognostic models were validated in an external cohort.

RESULTS
A total of 2035 patients were included in the analysis. A total of 33 genes had driver mutations in at least 5 patients, with mutations in JAK2, CALR, or MPL being the sole abnormality in 45% of the patients. The numbers of driver mutations increased with age and advanced disease. Driver mutations, germline polymorphisms, and demographic variables independently predicted whether patients received a diagnosis of essential thrombocythemia as compared with polycythemia vera or a diagnosis of chronic-phase disease as compared with myelofibrosis. We defined eight genomic subgroups that showed distinct clinical phenotypes, including blood counts, risk of leukemic transformation, and event-free survival. Integrating 63 clinical and genomic variables, we created prognostic models capable of generating personally tailored predictions of clinical outcomes in patients with chronic-phase myeloproliferative neoplasms and myelofibrosis. The predicted and observed outcomes correlated well in internal cross-validation of a training cohort and in an independent external cohort. Even within individual categories of existing prognostic schemas, our models substantially improved predictive accuracy.

CONCLUSIONS
Comprehensive genomic characterization identified distinct genetic subgroups and provided a classification of myeloproliferative neoplasms on the basis of causal biologic mechanisms. Integration of genomic data with clinical variables enabled the personalized predictions of patients’ outcomes and may support the treatment of patients with myeloproliferative neoplasms. (Funded by the Wellcome Trust and others.)
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Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth

Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth | PARP Inhibitors Cancer Review | Scoop.it
Brief Communication...
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IL-8-induced O -GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells

IL-8-induced O -GlcNAc modification via GLUT3 and GFAT regulates cancer stem cell-like properties in colon and lung cancer cells | PARP Inhibitors Cancer Review | Scoop.it
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SWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A -mutated cells

SWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A -mutated cells | PARP Inhibitors Cancer Review | Scoop.it
The mechanism of resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations is unknown. Here, the authors demonstrate that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated ovarian cancer cells.
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Cancer origins—genetics rules the day

Cancer origins—genetics rules the day | PARP Inhibitors Cancer Review | Scoop.it
Summary
A major goal of cancer research is to identify central molecular and cellular mechanisms underlying the development of tumors and their response to treatment, with the aim of uncovering key vulnerabilities. Early events in the development of cancer may inform such vulnerabilities (1), but early tumors are much more difficult to observe and study in patients than established tumors. Indeed, one of the hardest issues to resolve in early tumor development is the relative contributions of the oncogenic driver mutations and the nonpathogenic gene networks expressed in a precancerous cell. On page 91 of this issue, Park et al. (2) investigate the mechanisms of development of neuro endocrine cancer in the lung and the prostate using human epithelial cells in culture. They find that these neuroendocrine tumors can arise from non-neuroendocrine epithelial cells, which converge upon reprogramming toward a neuroendocrine fate via a common and specific combination of genetic factors.

http://www.sciencemag.org/about/science-licenses-journal-article-reuse
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Analysis of cell proliferation and tissue remodelling uncovers a KLF4 activity score associated with poor prognosis in colorectal cancer

Analysis of cell proliferation and tissue remodelling uncovers a KLF4 activity score associated with poor prognosis in colorectal cancer | PARP Inhibitors Cancer Review | Scoop.it
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