Re-programing Chromatin with a Bifunctional LSD1/HDAC Inhibitor Induces Therapeutic Differentiation in DIPG
Publication date: Available online 17 October 2019Source: Cancer CellAuthor(s): Jamie N. Anastas, Barry M. Zee, Jay H. Kalin, Mirhee Kim, Robyn Guo, Sanda Alexandrescu, Mario Andres Blanco, Stefanie Giera, Shawn M. Gillespie, Jayanta Das, Muzhou Wu, Sarah Nocco, Dennis M. Bonal, Quang-De Nguyen, Mario L. Suva, Bradley E. Bernstein, Rhoda Alani, Todd R. Golub, Philip A. Cole, Mariella G. FilbinSummaryH3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysin...
Source: Cancer Cell - October 18, 2019 Category: Cancer & Oncology Source Type: research

Venetoclax in Lymphoid Malignancies: New Insights, More to Learn
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Rachel Thijssen, Andrew W. RobertsIn this issue of Cancer Cell, Guièza et al. describe that overexpression of the pro-survival protein MCL1 and cellular energy metabolic reprogramming can contribute to resistance to the BCL2 inhibitor venetoclax in patients with chronic lymphocytic leukemia. This adds a new dimension to understanding of secondary clinical resistance to venetoclax. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

PRC2 Plays Red Light, Green Light with MHC-I and CD8+ T Cells
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Johnathan R. WhetstineIn this issue of Cancer Cell, Burr et al. report that PRC2 plays a conserved role in silencing antigen presentation and processing genes and, in turn, CD8+ T cell activation. Furthermore, PRC2-targeted therapeutics overcome gene silencing and promote tumor clearance by cytotoxic T cells. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Thrown for a Loop: Awakening BORIS to Evade ALK Inhibition Therapy
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Esther R. Berko, Yael P. MosséMechanisms of acquired resistance to ALK inhibition therapy in neuroblastoma have not yet been elucidated. In a recent issue of Nature, Debruyne et al. demonstrate that resistant MYCN-amplified ALK-mutated neuroblastoma cells overexpress BORIS, resulting in wide-ranging changes in chromatin interaction and transcriptional reprogramming. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Acquired Resistance Is Oncogene and Drug Agnostic
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Robert C. DoebeleRecent approvals of TRK inhibitors have demonstrated the success of a tumor agnostic approach to oncogene-targeted therapy across cancers. Collective data from acquired resistance studies suggest that resistance mechanisms, which include both kinase domain mutations and bypass signaling via RTK-RAS-RAF-MAPK pathways, frequently recur regardless of tumor type, oncogene, and drug. (Source: Cancer Cell)
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Toward the Early Detection of Cancer by Decoding the Epigenetic and Environmental Fingerprints of Cell-Free DNA
Publication date: 14 October 2019Source: Cancer Cell, Volume 36, Issue 4Author(s): Ymke van der Pol, Florent MouliereWidespread adaptation of liquid biopsy for the early detection of cancer has yet to reach clinical utility. Circulating tumor DNA is commonly detected though the presence of genetic alterations, but only a minor fraction of tumor-derived cell-free DNA (cfDNA) fragments exhibit mutations. The cellular processes occurring in cancer development mark the chromatin. These epigenetic marks are reflected by modifications in the cfDNA methylation, fragment size, and structure. In this review, we describe how going b...
Source: Cancer Cell - October 15, 2019 Category: Cancer & Oncology Source Type: research

Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
Publication date: Available online 3 October 2019Source: Cancer CellAuthor(s): Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark RoutbortSummaryWe characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven E...
Source: Cancer Cell - October 5, 2019 Category: Cancer & Oncology Source Type: research

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer
Publication date: Available online 3 October 2019Source: Cancer CellAuthor(s): Lichun Ma, Maria O. Hernandez, Yongmei Zhao, Monika Mehta, Bao Tran, Michael Kelly, Zachary Rae, Jonathan M. Hernandez, Jeremy L. Davis, Sean P. Martin, David E. Kleiner, Stephen M. Hewitt, Kris Ylaya, Bradford J. Wood, Tim F. Greten, Xin Wei WangSummaryCellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and betw...
Source: Cancer Cell - October 5, 2019 Category: Cancer & Oncology Source Type: research

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer
Publication date: Available online 26 September 2019Source: Cancer CellAuthor(s): Marian L. Burr, Christina E. Sparbier, Kah Lok Chan, Yih-Chih Chan, Ariena Kersbergen, Enid Y.N. Lam, Elizabeth Azidis-Yates, Dane Vassiliadis, Charles C. Bell, Omer Gilan, Susan Jackson, Lavinia Tan, Stephen Q. Wong, Sebastian Hollizeck, Ewa M. Michalak, Hannah V. Siddle, Michael T. McCabe, Rab K. Prinjha, Glen R. Guerra, Benjamin J. SolomonSummaryLoss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb re...
Source: Cancer Cell - September 27, 2019 Category: Cancer & Oncology Source Type: research

Dynamic Incorporation of Histone H3 Variants into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization
Publication date: Available online 26 September 2019Source: Cancer CellAuthor(s): Ana P. Gomes, Didem Ilter, Vivien Low, Adam Rosenzweig, Zih-Jie Shen, Tanya Schild, Martin A. Rivas, Ekrem E. Er, Dylan R. McNally, Anders P. Mutvei, Julie Han, Yi-Hung Ou, Paola Cavaliere, Edouard Mullarky, Michal Nagiec, Sejeong Shin, Sang-Oh Yoon, Noah Dephoure, Joan Massagué, Ari M. MelnickSummaryMetastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation. Here...
Source: Cancer Cell - September 27, 2019 Category: Cancer & Oncology Source Type: research

Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants
Publication date: Available online 19 September 2019Source: Cancer CellAuthor(s): Christopher A. Eide, Matthew S. Zabriskie, Samantha L. Savage Stevens, Orlando Antelope, Nadeem A. Vellore, Hein Than, Anna Reister Schultz, Phillip Clair, Amber D. Bowler, Anthony D. Pomicter, Dongqing Yan, Anna V. Senina, Wang Qiang, Todd W. Kelley, Philippe Szankasi, Michael C. Heinrich, Jeffrey W. Tyner, Delphine Rea, Jean-Michel Cayuela, Dong-Wook KimSummaryBCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved ...
Source: Cancer Cell - September 20, 2019 Category: Cancer & Oncology Source Type: research

Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies
Publication date: Available online 19 September 2019Source: Cancer CellAuthor(s): Romain Guièze, Vivian M. Liu, Daniel Rosebrock, Alexis A. Jourdain, María Hernández-Sánchez, Aina Martinez Zurita, Jing Sun, Elisa Ten Hacken, Kaitlyn Baranowski, Philip A. Thompson, Jin-Mi Heo, Zachary Cartun, Ozan Aygün, J. Bryan Iorgulescu, Wandi Zhang, Giulia Notarangelo, Dimitri Livitz, Shuqiang Li, Matthew S. Davids, Anat BiranSummaryMitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show tha...
Source: Cancer Cell - September 20, 2019 Category: Cancer & Oncology Source Type: research

LMO2 as a Biomarker for Hypersensitivity to Genotoxic Therapy
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Claudio Scuoppo, Shan ZhaIn this issue of Cancer Cell, Parvin and colleagues identify the expression of LMO2 as a biomarker for DNA repair defects in lymphomas. Using isogenic cell lines and xenografts, the authors show that expression of LMO2 predicts sensitivity to PARP inhibition, especially in combination with genotoxic therapy. (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Colon Cancer: Epithelial Notch Signaling Recruits Neutrophils to Drive Metastasis
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Jürgen RulandIn this issue of Cancer Cell, Jackstadt et al. report that pathological Notch signaling in colorectal cancer (CRC) cells can initiate a neutrophil-dependent, TGF-β-mediated cascade that leads to metastatic disease. Inhibition of this pathway with clinically relevant compounds blocks metastatic spread in a developed murine model of CRC. (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research

Recruit or Reboot? How Does Anti-PD-1 Therapy Change Tumor-Infiltrating Lymphocytes?
Publication date: 16 September 2019Source: Cancer Cell, Volume 36, Issue 3Author(s): Margaret K. Callahan, Jedd D. WolchokIt has been widely assumed that PD-1 blockade works by reinvigorating (“rebooting”) pre-existing exhausted tumor-infiltrating ilymphocytes (TILs). A recent study challenges this paradigm, demonstrating that the majority of tumor-specific TILs after anti-PD-1 treatment have TCRs not identified in the tumor pre-therapy, suggesting they are newly recruited post-therapy. (Source: Cancer Cell)
Source: Cancer Cell - September 17, 2019 Category: Cancer & Oncology Source Type: research