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Paracrine placental growth factor signaling in response to ionizing radiation is p53-dependent and contributes to radioresistance Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-22 Tamara Kazimova, Fabienne Tschanz, Ashish Sharma, Irma Telarovic, Marco Wachtel, Gloria Pedot, Beat Schafer, Martin N Pruschy
Placental growth factor (PlGF) is a pro-angiogenic, N-glycosylated growth factor, which is secreted under pathological situations. Here, we investigated the regulation of PlGF in response to ionizing radiation (IR) and its role for tumor angiogenesis and radiosensitivity. Secretion and expression of PlGF was induced in multiple tumor cell lines (medulloblastoma, colon and lung adenocarcinoma) in response
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Loss of 9p21 regulatory hub promotes kidney cancer progression by upregulating HOXB13 Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-22 Maria Francesca Baietti, Peihua Zhao, Jonathan Crowther, Raj Nayan Sewduth, Linde De Troyer, Maria Debiec-Rychter, Anna A Sablina
Loss of chromosome 9p21 is observed in one-thirds of clear cell renal cell carcinoma (ccRCC) and associated with poorer patient survival. Unexpectedly, 9p21 loss-of-heterozygosity (LOH) does not lead to decreased expression of the 9p21 tumor suppressor genes, CDKN2A and CDKN2B, suggesting alternative mechanisms of 9p-mediated tumorigenesis. Concordantly, CRISPR-mediated 9p21 deletion promotes growth
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Comprehensive mutational analysis of the BRCA1-associated DNA helicase and tumor suppressor, FANCJ/BACH1/BRIP1 Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-22 Jennifer A. Calvo, Briana Fritchman, Desiree Hernandez, Nicole S Persky, Cory M Johannessen, Federica Piccioni, Brian A Kelch, Sharon B. Cantor
FANCJ (BRIP1/BACH1) is a hereditary breast and ovarian cancer (HBOC) gene encoding a DNA helicase. Similar to HBOC genes, BRCA1 and BRCA2, FANCJ is critical for processing DNA inter-strand crosslinks (ICL) induced by chemotherapeutics, such as cisplatin. Consequently, cells deficient in FANCJ or its catalytic activity are sensitive to ICL-inducing agents. Unfortunately, the majority of FANCJ clinical
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Long Noncoding RNA NEAT1 Acts as a Molecular Switch for BRD4 Transcriptional Activity and Mediates Repression of BRD4/WDR5 Target Genes Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-19 Mariaelena Pistoni, Teresa Rossi, Benedetta Donati, Federica Torricelli, Maurizio Polano, Alessia Ciarrocchi
BRD4 is an epigenome reader known to exert key roles at the interface between chromatin remodeling and transcriptional regulation, and is primarily known for its role in promoting gene expression. In selective contexts, however, BRD4 may work as negative regulator of transcription. Here, we reported that BRD4 binds several long noncoding RNAs (lncRNA). Among these, the lncRNA NEAT1 was found to interfere
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Functional Hierarchy and Cooperation of EMT Master Transcription Factors in Breast Cancer Metastasis Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-19 Joseph B. Addison, Maria A. Voronkova, James H. Fugett, Chen-Chung Lin, Nathaniel C. Linville, Brandon Trinh, Ryan H. Livengood, Matthew B. Smolkin, Michael D. Schaller, J. Michael Ruppert, Elena N. Pugacheva, Chad J. Creighton, Alexey V. Ivanov
Several master transcription factors (TF) can activate the epithelial-to-mesenchymal transition (EMT). However, their individual and combinatorial contributions to EMT in breast cancer are not defined. We show that overexpression of EMT-TFs individually in epithelial cells upregulated endogenous SNAI2, ZEB1/2, TCF4, and TWIST1/2 as a result of positive feedback mediated in part by suppression of their
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Colorectal cancer-associated Smad4 R361 hotspot mutations boost Wnt/{beta}-catenin signaling through enhanced Smad4-LEF1 binding Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-19 Claudia B Lanauze, Priyanka Sehgal, Katharina Hayer, Manuel Torres-Diz, James A Pippin, Struan F A Grant, Andrei Thomas-Tikhonenko
10-30% of colorectal cancer (CRC) patients harbor either loss of or missense mutations in SMAD4, a critical component of the TGFβ signaling pathway. The pathophysiological function of missense mutations in Smad4 is not fully understood. They usually map to the MH2 domain, specifically to residues that are involved in heterodimeric complex formation with regulatory Smads (such as Smad2/3) and ensuing
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Colorectal cancer-derived CAT1-positive extracellular vesicles alter nitric oxide metabolism in endothelial cells and promote angiogenesis Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-19 Atsushi Ikeda, Satoshi Nagayama, Makoto Sumazaki, Makoto Konishi, Risa Fujii, Naomi Saichi, Satoshi Muraoka, Daisuke Saigusa, Hideaki Shimada, Yoshiharu Sakai, Koji Ueda
Accumulating scientific evidences strongly support the importance of cancer-derived extracellular vesicles (EVs) in organization of tumor microenvironment and metastatic niches, which are also considered as ideal tools for cancer liquid biopsy. To uncover the full scope of proteomic information packaged within EVs secreted directly from human colorectal cancer (CRC), we cultured surgically-resected
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O-GlcNAc Transferase - An Auxiliary Factor or a Full-blown Oncogene? Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-19 Harri M. Itkonen, Massimo Loda, Ian G. Mills
The β-linked N-acetyl-d-glucosamine (GlcNAc) is a posttranslational modification of serine and threonine residues catalyzed by the enzyme O-GlcNAc transferase (OGT). Increased OGT expression is a feature of most human cancers and inhibition of OGT decreases cancer cell proliferation. Antiproliferative effects are attributed to posttranslational modifications of known regulators of cancer cell proliferation
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Molecular determinants of medulloblastoma metastasis and leptomeningeal dissemination Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-19 Min Li, Yuhao Deng, Wangming Zhang
Medulloblastoma (MB) is the most common malignant brain cancer in pediatrics consisting of four molecular subgroups, namely wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. One of the biggest challenges in the clinical management of this disease is the leptomeningeal dissemination (LMD) of tumor cells with high morbidity and mortality. Many molecular regulators to date have been identified
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Adaptor Protein ShcD/SHC4 Interacts with Tie2 Receptor to Synergistically Promote Glioma Cell Invasion Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-16 Manali Tilak, Begüm Alural, Sarah E. Wismer, Megan I. Brasher, Laura A. New, Steven D. Sheridan, Roy H. Perlis, Marc G. Coppolino, Jasmin Lalonde, Nina Jones
Gliomas are characterized by diffuse infiltration of tumor cells into surrounding brain tissue, and this highly invasive nature contributes to disease recurrence and poor patient outcomes. The molecular mechanisms underlying glioma cell invasion remain incompletely understood, limiting development of new targeted therapies. Here, we have identified phosphotyrosine adaptor protein ShcD as upregulated
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Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in ApcS580/+; KrasG12D/+ Mice Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-16 Huajun Han, Laurie A. Davidson, Martha Hensel, Grace Yoon, Kerstin Landrock, Clinton Allred, Arul Jayaraman, Ivan Ivanov, Stephen H. Safe, Robert S. Chapkin
The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of “cooperation response genes” to modulate the function of cancer “driver” genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal
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mDKN-01, a Novel Anti-DKK1 mAb, Enhances Innate Immune Responses in the Tumor Microenvironment Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-16 Michael S. Haas, Michael H. Kagey, Heidi Heath, Franziska Schuerpf, James B. Rottman, Walter Newman
Dickkopf-1 (DKK1), a secreted modulator of Wnt signaling, is overexpressed in many cancers, is often associated with worse clinical outcomes, and has been shown to have immunosuppressive effects. DKN-01 is an IgG4 clinical stage antibody that potently and specifically neutralizes human and murine DKK1 and has recently completed a promising study in combination with pembrolizumab in patients with g
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Old Dog, New Trick: Type I IFN-based Treatment for Acute Myeloid Leukemia Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-16 Abdullah Alsufyani, Rehab Alanazi, John F. Woolley, Lekh N. Dahal
Despite strong biological rationale for the use of type-I IFNs for the treatment of acute myeloid leukemia (AML), their usage is limited to few hematologic malignancies. Here, we propose that innate immune sensing machinery, particularly the stimulator of IFN genes pathway, may be exploited to deliver antileukemic effects in AML.
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Palbociclib Renders Human Papilloma Virus-Negative Head and Neck Squamous Cell Carcinoma Vulnerable to the Senolytic Agent Navitoclax Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-16 Nicholas J. Gadsden, Cory D. Fulcher, Daniel Li, Nitisha Shrivastava, Carlos Thomas, Jeffrey E. Segall, Michael B. Prystowsky, Nicolas F. Schlecht, Evripidis Gavathiotis, Thomas J. Ow
We demonstrate that inhibition of cyclin-dependent kinases 4/6 (CDK4/6) leads to senescence in human papillomavirus (HPV)–negative (−) head and neck squamous cell carcinoma (HNSCC), but not in HPV-positive (+) HNSCC. The BCL-2 family inhibitor, navitoclax, has been shown to eliminate senescent cells effectively. We evaluated the efficacy of combining palbociclib and navitoclax in HPV− HNSCC. Three
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AraC-FdUMP[10] (CF10) is a next generation fluoropyrimidine with potent antitumor activity in PDAC and synergy with PARG inhibition Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-16 Alex O Haber, Aditi Jain, Chinnadurai Mani, Avinoam Nevler, Lebaron C Agostini, Talia Golan, Komaraiah Palle, Charles J. Yeo, William H. Gmeiner, Jonathan R. Brody
CF10 is a 2nd generation polymeric fluoropyrimidine (FP) that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard of care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple
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Crenolanib regulates ERK and AKT/mTOR signaling pathways in RAS/BRAF-mutated colorectal cancer cells and organoids Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-12 Shiki Fujino, Norikatsu Miyoshi, Aya Ito, Masayoshi Yasui, Masayuki Ohue, Takayuki Ogino, Hidekazu Takahashi, Mamoru Uemura, Chu Matsuda, Tsunekazu Mizushima, Yuichiro Doki, Hidetoshi Eguchi
Recently developed molecularly-targeted therapies such as EGFR inhibitors have notably improved the prognosis of patients with cancer. However, patients with KRAS and BRAF mutations do not currently benefit from these therapies. Here, we aimed to examine potential effects of crenolanib as a new molecularly-targeted therapy in colorectal cancer (CRC). We used multiple CRC cell lines to investigate the
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Silencing of SmgGDS, a novel mTORC1 inducer that binds to RHEBs, inhibits malignant mesothelioma cell proliferation Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-11 Tatsuhiro Sato, Satomi Mukai, Haruna Ikeda, Emi Mishiro-Sato, Ken Akao, Toshiyuki Kobayashi, Okio Hino, Wataru Shimono, Yoshio Shibagaki, Seisuke Hattori, Yoshitaka Sekido
Malignant mesothelioma (MM) is an aggressive tumor that typically develops after a long latency following asbestos exposure. Although mechanistic target of rapamycin complex 1 (mTORC1) activation enhances MM cell growth, the mTORC1 inhibitor everolimus has shown limited efficacy in clinical trials of MM patients. We explored the mechanism underlying mTORC1 activation in MM cells and its effects on
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Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-09 Marjolaine Bauzone, Mouloud Souidi, Anne-Frédérique Dessein, Maxence Wisztorski, Audrey Vincent, Jean-Pascal Gimeno, Didier Monté, Isabelle Van Seuningen, Christian Gespach, Guillemette Huet
The mechanisms whereby the Hippo pathway effector YAP regulates cancer cell stemness, plasticity, and chemoresistance are not fully understood. We previously showed that in 5-fluorouracil (5-FU)–resistant colorectal cancer cells, the transcriptional coactivator YAP is differentially regulated at critical transitions connected with reversible quiescence/dormancy to promote metastasis. Here, we found
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Exosomal Delivery of FTO Confers Gefitinib Resistance to Recipient Cells through ABCC10 Regulation in an m6A-dependent Manner Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-09 Peng Xiao, Yu-kang Liu, Wei Han, Yan Hu, Bo-you Zhang, Wen-liang Liu
Gefitinib is suitable for the treatment of locally advanced or metastatic non–small cell lung cancer. However, the development of acquired resistance limits its long-term efficacy in regardless of significant clinical benefit to patients. Therefore, to elucidate the mechanism of gefitinib resistance in addition to target gene mutation may greatly increase its clinical efficacy. It was found first that
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Molecular Profiling of Metastatic Bladder Cancer Early-Phase Clinical Trial Participants Predicts Patient Outcomes Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-09 Omar Alhalabi, Andrew W. Hahn, Pavlos Msaouel, Alexander Y. Andreev-Drakhlin, Funda Meric-Bernstam, Aung Naing, Sarina Piha-Paul, Janku Filip, Shubham Pant, Timothy A. Yap, David S. Hong, Siqing Fu, Daniel Karp, Erick Campbell, Hung Le, Matthew T. Campbell, Amishi Y. Shah, Nizar M. Tannir, Arlene O. Siefker-Radtke, Jianjun Gao, Jason Roszik, Vivek Subbiah
Prognosis for patients with metastatic bladder carcinoma (mBC) remains limited and in need of novel therapies. We retrospectively analyzed medical records of 43 patients with platinum-refractory metastatic bladder cancer (mBC) who participated in one or more phase I trials of various investigational therapies. Patients' tumors or circulating tumor DNA were analyzed by next-generation sequencing. The
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Metabolic Regulator IAPP (Amylin) Is Required for BRAF and RAS Oncogene-Induced Senescence Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-09 Sam Garnett, Angeline de Bruyns, Veronique Provencher-Tom, Kendall Dutchak, Ran Shu, David Dankort
Cellular senescence is characterized by a prolonged and predominantly irreversible cell-cycle arrest state, which is linked to loss of tissue function and aging in mammals. Moreover, in response to aberrant oncogenic signals such as those from oncogenic RAS or BRAF, senescence functions as an intrinsic tumor suppressor mechanism restraining tumor progression. In addition to this durable proliferative
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5-Azacytidine Transiently Restores Dysregulated Erythroid Differentiation Gene Expression in TET2-Deficient Erythroleukemia Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-04 Brian M. Reilly, Timothy Luger, Soo Park, Chan-Wang Jerry Lio, Edahí González-Avalos, Emily C. Wheeler, Minjung Lee, Laura Williamson, Tiffany Tanaka, Dinh Diep, Kun Zhang, Yun Huang, Anjana Rao, Rafael Bejar
DNA methyltransferase inhibitors (DNMTI) like 5-Azacytidine (5-Aza) are the only disease-modifying drugs approved for the treatment of higher-risk myelodysplastic syndromes (MDS), however less than 50% of patients respond, and there are no predictors of response with clinical utility. Somatic mutations in the DNA methylation regulating gene tet-methylcytosine dioxygenase 2 ( TET2 ) are associated with
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The MEK/ERK Network as a Therapeutic Target in Human Cancer Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-04 Renee Barbosa, Lucila A. Acevedo, Ronen Marmorstein
The RAS–RAF–MEK–ERK pathway is the most well-studied of the MAPK cascades and is critical for cell proliferation, differentiation, and survival. Abnormalities in regulation resulting from mutations in components of this pathway, particularly in upstream proteins, RAS and RAF, are responsible for a significant fraction of human cancers and nearly all cutaneous melanomas. Activation of receptor tyrosine
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The Ubiquitin-Specific Peptidase USP18 Promotes Lipolysis, Fatty Acid Oxidation, and Lung Cancer Growth Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-02 Xi Liu, Yun Lu, Zibo Chen, Xiuxia Liu, Weiguo Hu, Lin Zheng, Yulong Chen, Jonathan M. Kurie, Mi Shi, Lisa Maria Mustachio, Thorkell Adresson, Stephen Fox, Jason Roszik, Masanori Kawakami, Sarah J. Freemantle, Ethan Dmitrovsky
Ubiquitin specific peptidase 18 (USP18), previously known as UBP43, is the IFN-stimulated gene 15 (ISG15) deconjugase. USP18 removes ISG15 from substrate proteins. This study reports that USP18-null mice (vs. wild-type mice) exhibited lower lipolysis rates, altered fat to body weight ratios, and cold sensitivity. USP18 is a regulator of lipid and fatty acid metabolism. Prior work established that USP18
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ILT3 (LILRB4) Promotes the Immunosuppressive Function of Tumor-Educated Human Monocytic Myeloid-Derived Suppressor Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-02 Latika Singh, Eric S. Muise, Anannya Bhattacharya, Jeff Grein, Sarah Javaid, Peter Stivers, Jun Zhang, Yujie Qu, Barbara Joyce-Shaikh, Andrey Loboda, Chunsheng Zhang, Michael Meehl, Derek Y. Chiang, Sheila H. Ranganath, Michael Rosenzweig, Philip E. Brandish
Myeloid-derived suppressor cells (MDSC) are immature myeloid cells that accumulate in the tumor microenvironment (TME). MDSCs have been shown to dampen antitumor immune responses and promote tumor growth; however, the mechanisms of MDSC induction and their role in promoting immune suppression in cancer remain poorly understood. Here, we characterized the phenotype and function of monocytic MDSCs (M-MDSC)
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Studying Immunotherapy Resistance in a Melanoma Autologous Humanized Mouse Xenograft Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 J. Jason Morton, Nathaniel Alzofon, Stephen B. Keysar, Tugs-Saikhan Chimed, Julie Reisinger, Loni Perrenoud, Phuong N. Le, Cera Nieto, Karina Gomez, Bettina Miller, Randi Yeager, Dexiang Gao, Aik-Choon Tan, Hilary Somerset, Theresa Medina, Xiao-Jing Wang, Jing H. Wang, William Robinson, Dennis R. Roop, Rene Gonzalez, Antonio Jimeno
Resistance to immunotherapy is a significant challenge, and the scarcity of human models hinders the identification of the underlying mechanisms. To address this limitation, we constructed an autologous humanized mouse (aHM) model with hematopoietic stem and progenitor cells (HSPC) and tumors from 2 melanoma patients progressing to immunotherapy. Unlike mismatched humanized mouse (mHM) models, generated
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Breast Tumor Kinase (Brk/PTK6) Mediates Advanced Cancer Phenotypes via SH2-Domain Dependent Activation of RhoA and Aryl Hydrocarbon Receptor (AhR) Signaling Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Amy R. Dwyer, Carlos Perez Kerkvliet, Raisa I. Krutilina, Hilaire C. Playa, Deanna N. Parke, Warner A. Thomas, Branden A. Smeester, Branden S. Moriarity, Tiffany N. Seagroves, Carol A. Lange
Protein tyrosine kinase 6 (PTK6; also called Brk) is overexpressed in 86% of patients with breast cancer; high PTK6 expression predicts poor outcome. We reported PTK6 induction by HIF/GR complexes in response to either cellular or host stress. However, PTK6-driven signaling events in the context of triple-negative breast cancer (TNBC) remain undefined. In a mouse model of TNBC, manipulation of PTK6
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SHOC2 Is a Critical Modulator of Sensitivity to EGFR-TKIs in Non-Small Cell Lung Cancer Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Hideki Terai, Junko Hamamoto, Katsura Emoto, Takeshi Masuda, Tadashi Manabe, Satoshi Kuronuma, Keigo Kobayashi, Keita Masuzawa, Shinnosuke Ikemura, Sohei Nakayama, Ichiro Kawada, Yusuke Suzuki, Osamu Takeuchi, Yukio Suzuki, Sumio Ohtsuki, Hiroyuki Yasuda, Kenzo Soejima, Koichi Fukunaga
EGFR mutation-positive patients with non–small cell lung cancer (NSCLC) respond well to treatment with EGFR–tyrosine kinase inhibitors (EGFR–TKI); however, treatment with EGFR–TKIs is not curative, owing to the presence of residual cancer cells with intrinsic or acquired resistance to this class of drugs. Additional treatment targets that may enhance the efficacy of EGFR–TKIs remain elusive. Using
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SLX4IP Promotes Telomere Maintenance in Androgen Receptor-Independent Castration-Resistant Prostate Cancer through ALT-like Telomeric PML Localization Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Tawna L. Mangosh, Wisam N. Awadallah, Magdalena M. Grabowska, Derek J. Taylor
In advanced prostate cancer, resistance to androgen deprivation therapy is achieved through numerous mechanisms, including loss of the androgen receptor (AR) allowing for AR-independent growth. Therapeutic options are limited for AR-independent castration-resistant prostate cancer (CRPC), and defining mechanisms critical for survival is of utmost importance for targeting this lethal disease. Our studies
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Intraperitoneal Oil Application Causes Local Inflammation with Depletion of Resident Peritoneal Macrophages Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Elisenda Alsina-Sanchis, Ronja Mülfarth, Iris Moll, Carolin Mogler, Juan Rodriguez-Vita, Andreas Fischer
Oil is frequently used as a solvent to inject lipophilic substances into the peritoneum of laboratory animals. Although mineral oil causes chronic peritoneal inflammation, little is known whether other oils are better suited. We show that olive, peanut, corn, or mineral oil causes xanthogranulomatous inflammation with depletion of resident peritoneal macrophages. However, there were striking differences
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A Role for the Autophagic Receptor, SQSTM1/p62, in Trafficking NF-{kappa}B/RelA to Nucleolar Aggresomes Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Ian T. Lobb, Pierre Morin, Kirsty Martin, Hazel C. Thoms, Jimi C. Wills, Xhordi Lleshi, Karl C.F. Olsen, Rory R. Duncan, Lesley A. Stark
Elevated NF-κB activity is a contributory factor in many hematologic and solid malignancies. Nucleolar sequestration of NF-κB/RelA represses this elevated activity and mediates apoptosis of cancer cells. Here, we set out to understand the mechanisms that control the nuclear/nucleolar distribution of RelA and other regulatory proteins, so that agents can be developed that specifically target these proteins
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FBW7 Inhibits Myeloid Differentiation in Acute Myeloid Leukemia via GSK3-Dependent Ubiquitination of PU.1 Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Mukul Mishra, Gatha Thacker, Akshay Sharma, Anil Kumar Singh, Vishal Upadhyay, Sabyasachi Sanyal, Shailendra Prasad Verma, Anil Kumar Tripathi, Madan Lal Brahma Bhatt, Arun Kumar Trivedi
Glycogen synthase kinase 3β (GSK3β), an ubiquitously expressed serine/threonine kinase is reported to be overexpressed and hyperactivated in cancers including acute myeloid leukemia (AML) where it promotes self-renewal, growth, and survival of AML cells. Therefore, GSK3β inhibition results in AML cell growth inhibition and myeloid differentiation. Here we identified master transcription factor PU.1
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Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Manman Deng, Zijun Y. Xu-Monette, Lan V. Pham, Xudong Wang, Alexandar Tzankov, Xiaosheng Fang, Feng Zhu, Carlo Visco, Govind Bhagat, Karen Dybkaer, April Chiu, Wayne Tam, Youli Zu, Eric D. Hsi, Hua You, Jooryung Huh, Maurilio Ponzoni, Andrés J.M. Ferreri, Michael B. Møller, Benjamin M. Parsons, Fredrick Hagemeister, J. Han van Krieken, Miguel A. Piris, Jane N. Winter, Yong Li, Bing Xu, Phillip Liu
Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC / BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities ( MYC rearrangement and/or Myc protein overexpression)
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Palmitate-Induced IRE1-XBP1-ZEB Signaling Represses Desmoplakin Expression and Promotes Cancer Cell Migration Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Aritro Nath, Amrita Oak, Kevin Y. Chen, Irene Li, R. Chauncey Splichal, Jason Portis, Sean Foster, S. Patrick Walton, Christina Chan
Elevated uptake of saturated fatty acid palmitate is associated with metastatic progression of cancer cells; however, the precise signaling mechanism behind the phenomenon is unclear. The loss of cell adhesion proteins, such as desmoplakin (DSP), is a key driving event in the transformation of cancer cells to more aggressive phenotypes. Here, we investigated the mechanism by which palmitate induces
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Transcriptomic Analysis of Diffuse Intrinsic Pontine Glioma (DIPG) Identifies a Targetable ALDH-Positive Subset of Highly Tumorigenic Cancer Stem-like Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Rachel K. Surowiec, Sarah F. Ferris, April Apfelbaum, Carlos Espinoza, Ranjit K. Mehta, Karamoja Monchamp, Veerin R. Sirihorachai, Karan Bedi, Mats Ljungman, Stefanie Galban
Understanding the cancer stem cell (CSC) landscape in diffuse intrinsic pontine glioma (DIPG) is desperately needed to address treatment resistance and identify novel therapeutic approaches. Patient-derived DIPG cells demonstrated heterogeneous expression of aldehyde dehydrogenase (ALDH) and CD133 by flow cytometry. Transcriptome-level characterization identified elevated mRNA levels of MYC, E2F ,
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Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Jeffim N. Kuznetsoff, Dawn A. Owens, Andy Lopez, Daniel A. Rodriguez, Nancy T. Chee, Stefan Kurtenbach, Daniel Bilbao, Evan R. Roberts, Claude-Henry Volmar, Claes Wahlestedt, Shaun P. Brothers, J. William Harbour
Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor-suppressor genes. BAP1 is one such tumor suppressor that is frequently inactivated in a variety of
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Combined Targeting of PARG and Wee1 Causes Decreased Cell Survival and DNA Damage in an S-Phase-Dependent Manner Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Lebaron C. Agostini, Aditi Jain, Alison Shupp, Avinoam Nevler, Grace McCarthy, Karen M. Bussard, Charles J. Yeo, Jonathan R. Brody
The DNA damage response (DDR) pathway sets the stage for tumorigenesis and provides both an opportunity for drug efficacy and resistance. Therapeutic approaches to target the DDR pathway include aiming to increase the efficacy of cytotoxic chemotherapies and synergistic drug strategies to enhance DNA damage, and hence cell death. Here, we report the first preclinical evaluation of a novel synergistic
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Exploiting Replication Stress as a Novel Therapeutic Intervention Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Jeffrey C. Martin, Tamara J. Hoegel, Miranda L. Lynch, Anna Woloszynska, Thomas Melendy, Joyce E. Ohm
Ewing sarcoma is an aggressive pediatric tumor of the bone and soft tissue. The current standard of care is radiation and chemotherapy, and patients generally lack targeted therapies. One of the defining molecular features of this tumor type is the presence of significantly elevated levels of replication stress as compared with both normal cells and many other types of cancers, but the source of this
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The Paradoxical Roles of Orphan Nuclear Receptor 4A (NR4A) in Cancer Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Stephen Safe, Keshav Karki
The three-orphan nuclear receptor 4A genes are induced by diverse stressors and stimuli, and there is increasing evidence that NR4A1 (Nur77), NR4A2 (Nurr1), and NR4A3 (Nor1) play an important role in maintaining cellular homeostasis and in pathophysiology. In blood-derived tumors (leukemias and lymphomas), NR4A expression is low and NR4A1−/−/NR4A3−/− double knockout mice rapidly develop acute myelocytic
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Cellular Functions of HPV16 E5 Oncoprotein during Oncogenic Transformation Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 Lourdes Gutierrez-Xicotencatl, Adolfo Pedroza-Saavedra, Lilia Chihu-Amparan, Azucena Salazar-Piña, Minerva Maldonado-Gama, Fernando Esquivel-Guadarrama
The human papillomavirus (HPV) is recognized as the main etiologic agent associated with cervical cancer. HPVs are epitheliotropic, and the ones that infect the mucous membranes are classified into low-risk (LR) and high-risk (HR) types. LR-HPVs produce benign lesions, whereas HR-HPVs produce lesions that may progress to cancer. HR-HPV types 16 and 18 are the most frequently found in cervical cancer
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Selected Articles from This Issue Mol. Cancer Res. (IF 4.63) Pub Date : 2021-02-01 American Association for Cancer Research
### [Alsina-Sanchis et al. Page 288][1] Intraperitoneal (i.p.) injection of experimental therapeutics is a common technique when assessing their bioactivity and efficacy in vivo . Many drugs are lipophilic and therefore require lipid carriers, such as mineral or vegetable oil, for delivery. It is
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Aberrant Induction of a Mesenchymal/Stem Cell Program Engages Senescence in Normal Mammary Epithelial Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Benjamin L. Bryson, Ilaria Tamagno, Sarah E. Taylor, Neetha Parameswaran, Noah M. Chernosky, Nikhila Balasubramaniam, Mark W. Jackson
Although frequently associated with tumor progression, inflammatory cytokines initially restrain transformation by inducing senescence, a key tumor-suppressive barrier. Here, we demonstrate that the inflammatory cytokine, oncostatin M, activates a mesenchymal/stem cell (SC) program that engages cytokine-induced senescence (CIS) in normal human epithelial cells. CIS is driven by Snail induction and
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LncIHAT Is Induced by Hypoxia-Inducible Factor 1 and Promotes Breast Cancer Progression Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Lin Chen, Lei Bao, Yanling Niu, Jennifer E. Wang, Ashwani Kumar, Chao Xing, Yingfei Wang, Weibo Luo
Hypoxia induces thousands of mRNAs and miRNAs to mediate tumor malignancy. However, hypoxia-induced long noncoding RNA (lncRNA) transcriptome and their role in triple-negative breast cancer (TNBC) have not been defined. Here we identified hypoxia-induced lncRNA transcriptome in two human TNBC cell lines by whole transcriptome sequencing. AC093818.1 was one of 26 validated lncRNAs and abundantly expressed
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Hypoxic Induction of Exosome Uptake through Proteoglycan-Dependent Endocytosis Fuels the Lipid Droplet Phenotype in Glioma Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Myriam Cerezo-Magaña, Helena C. Christianson, Toin H. van Kuppevelt, Karin Forsberg-Nilsson, Mattias Belting
As an adaptive response to hypoxic stress, aggressive tumors rewire their metabolic phenotype into increased malignant behavior through extracellular lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known
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Suppression of MET Signaling Mediated by Pitavastatin and Capmatinib Inhibits Oral and Esophageal Cancer Cell Growth Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Bo Xu, Tomoki Muramatsu, Johji Inazawa
Despite increasing knowledge on oral and esophageal squamous cell carcinoma (OSCC and ESCC), specific medicines against both have not yet been developed. Here, we aimed to find novel anticancer drugs through functional cell-based screening of an FDA-approved drug library against OSCC and ESCC. Pitavastatin, an HMGCR inhibitor, emerged as an anticancer drug that inhibits tumor growth by downregulating
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Preclinical evaluation of gilteritinib on NPM1-ALK driven Anaplastic Large Cell Lymphoma Cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Sudhakiranmayi Kuravi, Janice Cheng, Gabrielle Fangman, Kishore Polireddy, Sophia McCormick, Tara L Lin, Anurag K Singh, Sunil Abhyankar, Siddhartha Ganguly, Danny R. Welch, Roy A Jensen, Joseph P. McGuirk, Ramesh Balusu
Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL cases express the (nucleophosmin 1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The homodimerization of NPM1-ALK fusion protein mediates constitutive activation of the chimeric tyrosine kinase activity and downstream
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Protein Arginine Methyltransferase 5 (PRMT5) and the ERK1/2 & PI3K Pathways: A Case for PRMT5 Inhibition and Combination Therapies in Cancer Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Tzuriel Sapir, David Shifteh, Moshe Pahmer, Sanjay Goel, Radhashree Maitra
The ERK1/2 (RAS, RAF, MEK, ERK) and PI3K (PI3K, AKT, mTOR, PTEN) pathways are the chief signaling pathways for cellular proliferation, survival, and differentiation. Overactivation and hyperphosphorylation of the ERK1/2 & PI3K pathways is frequently observed in cancer and is associated with poor patient prognosis. While it is well known that genetic alterations lead to the dysregulation of the ERK1/2
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Relevance of the Bruton Tyrosine Kinase as a Target for COVID-19 Therapy Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Miran Rada, Zahraa Qusairy, Marta Massip-Salcedo, Salvador Macip
The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged as one of the biggest global health threats worldwide. As of October 2020, more than 44 million confirmed cases and more than 1,160,000 deaths have been reported globally, and the toll is likely to be much higher before the pandemic is over. There are currently little therapeutic options available and new potential targets are
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Phosphorylation and Driver Mutations in PI3K{alpha} and PTEN Autoinhibition Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Ruth Nussinov, Mingzhen Zhang, Chung-Jung Tsai, Hyunbum Jang
PI3K and PTEN are the second and third most highly mutated proteins in cancer following only p53. Their actions oppose each other. PI3K phosphorylates signaling lipid PIP2 to PIP3. PTEN dephosphorylates it back. Driver mutations in both proteins accrue PIP3. PIP3 recruits AKT and PDK1 to the membrane, promoting cell-cycle progression. Here we review phosphorylation events and mutations in autoinhibition
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Identification and Characterization of Cancer Cells That Initiate Metastases to the Brain and Other Organs Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Anna. S. Berghoff, Yunxiang Liao, Matthia A. Karreman, Ayseguel Ilhan-Mutlu, Katharina Gunkel, Martin R. Sprick, Christian Eisen, Tobias Kessler, Matthias Osswald, Susanne Wünsche, Manuel Feinauer, Brunhilde Gril, Frederic Marmé, Laura L. Michel, Zuszanna Bago-Horvath, Felix Sahm, Natalia Becker, Michael O. Breckwoldt, Gergely Solecki, Miriam Gömmel, Lulu Huang, Petra Rübmann, Carina M. Thome, Miriam
Specific biological properties of those circulating cancer cells that are the origin of brain metastases (BM) are not well understood. Here, single circulating breast cancer cells were fate-tracked during all steps of the brain metastatic cascade in mice after intracardial injection over weeks. A novel in vivo two-photon microscopy methodology was developed that allowed to determine the specific cellular
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Selective ERBB2 and BCL2 Inhibition is Synergistic for Mitochondrial-mediated Apoptosis in MDS and AML cells Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-29 Angel Y.F. Kam, Sadhna O. Piryani, Chang-Lung Lee, David A Rizzieri, Neil L. Spector, Stefanie Sarantopoulos, Phuong L. Doan
The ERBB2 proto-oncogene is associated with an aggressive phenotype in breast cancer. Its role in hematologic malignancies is incompletely defined, in part because ERBB2 is not readily detected on the surface of cancer cells. We demonstrate that truncated ERBB2, which lacks the extracellular domain, is overexpressed on primary CD34+ myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cells
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A New Pipeline to Predict and Confirm Tumor Neoantigens Predict Better Response to Immune Checkpoint Blockade Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-14 Yelena Lazdun, Han Si, Todd Creasy, Koustubh Ranade, Brandon W. Higgs, Katie Streicher, Nicholas M. Durham
Mutations that drive oncogenesis in cancer can generate neoantigens that may be recognized by the immune system. Identification of these neoantigens remains challenging due to the complexity of the MHC antigen and T-cell receptor interaction. Here, we describe the development of a systematic approach to efficiently identify and validate immunogenic neoantigens. Whole-exome sequencing of tissue from
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Omega-3 Eicosapentaenoic Acid Reduces Prostate Tumor Vascularity Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-14 Nikunj Gevariya, Gabriel Lachance, Karine Robitaille, Charles Joly Beauparlant, Lisanne Beaudoin, Éric Fournier, Yves Fradet, Arnaud Droit, Pierre Julien, André Marette, Alain Bergeron, Vincent Fradet
The impact of omega (ω)-3 fatty acids on prostate cancer is controversial in epidemiological studies but experimental studies suggest a protective effect. However, little is known about the mechanism of action. Here, we studied the effects of purified fatty acid molecules on prostate tumor progression using the TRAMP-C2 syngeneic immunocompetent mouse model. Compared with ω-6 or ω-9–supplemented animals
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N-Acetyl-L-cysteine Promotes Ex Vivo Growth and Expansion of Single Circulating Tumor Cells by Mitigating Cellular Stress Responses Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-14 Teng Teng, Mohamed Kamal, Oihana Iriondo, Yonatan Amzaleg, Chunqiao Luo, Amal Thomas, Grace Lee, Ching-Ju Hsu, John D. Nguyen, Irene Kang, James Hicks, Andrew Smith, Richard Sposto, Min Yu
Circulating tumor cells (CTC) can be isolated via a minimally invasive blood draw and are considered a “liquid biopsy” of their originating solid tumors. CTCs contain a small subset of metastatic precursors that can form metastases in secondary organs and provide a resource to identify mechanisms underlying metastasis-initiating properties. Despite technological advancements that allow for highly sensitive
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MYC Activity Inference Captures Diverse Mechanisms of Aberrant MYC Pathway Activation in Human Cancers Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-14 Evelien Schaafsma, Yanding Zhao, Lanjing Zhang, Yong Li, Chao Cheng
c-MYC (MYC) is deregulated in more than 50% of all cancers. While MYC amplification is the most common MYC-deregulating event, many other alterations can increase MYC activity. We thus systematically investigated MYC pathway activity across different tumor types. Using a logistic regression framework, we established tumor type–specific, transcriptomic-based MYC activity scores that can accurately capture
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G9a Promotes Invasion and Metastasis of Non-Small Cell Lung Cancer through Enhancing Focal Adhesion Kinase Activation via NF-{kappa}B Signaling Pathway Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-14 Ting Sun, Keqiang Zhang, Rajendra P. Pangeni, Jun Wu, Wendong Li, Yong Du, Yuming Guo, Shyambabu Chaurasiya, Leonidas Arvanitis, Dan J. Raz
Potential roles of euchromatic histone methyltransferase 2 ( EHMT2 or G9a) in invasion and metastasis are not well understood in non–small cell lung cancer (NSCLC). Here, we investigated the effect and underlying mechanisms of G9a and therapeutic implications of targeting G9a in the invasion and metastasis of NSCLC. Overexpression of G9a significantly enhanced in vitro proliferation and invasion, while
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The Heme-Regulated Inhibitor Pathway Modulates Susceptibility of Poor Prognosis B-Lineage Acute Leukemia to BH3-Mimetics Mol. Cancer Res. (IF 4.63) Pub Date : 2021-01-14 Kaitlyn H. Smith, Amit Budhraja, John Lynch, Kathryn Roberts, John C. Panetta, Jon P. Connelly, Meghan E. Turnis, Shondra M. Pruett-Miller, John D. Schuetz, Charles G. Mullighan, Joseph T. Opferman
Antiapoptotic MCL1 is one of the most frequently amplified genes in human cancers and elevated expression confers resistance to many therapeutics including the BH3-mimetic agents ABT-199 and ABT-263. The antimalarial, dihydroartemisinin (DHA) translationally represses MCL-1 and synergizes with BH3-mimetics. To explore how DHA represses MCL-1, a genome-wide CRISPR screen identified that loss of genes