bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia
Authors: Ding Ling-Wen , Sun Qiao-Yang , Tan Kar-Tong , Chien Wenwen , Thippeswamy Anand Mayakonda , Eng Juh Yeoh Allen , Kawamata Norihiko , Nagata Yasunobu , Xiao Jin-Fen , Loh Xin-Yi , Lin De-Chen , Garg Manoj , Jiang Yan-Yi , Xu Liang , Lim Su-Lin , Liu Li-Zhen , Madan Vikas , Sanada Masashi , Fernández Lucia Torres , Preethi Hema , Lill Michael , Kantarjian Hagop M. , Kornblau Steven M. , Miyano Satoru , Liang Der-Cherng , Ogawa Seishi , Shih Lee-Yung , Yang Henry , Koeffler H. Phillip
Published: March 2023

Abstract
Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) is mainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. Cancer Res; 77(2); 390–400. ©2016 AACR.
Data from Peripheral Neuropathy Induced by Microtubule-Targeted Chemotherapies: Insights into Acute Injury and Long-term Recovery
Authors: Wozniak Krystyna M. , Vornov James J. , Wu Ying , Liu Ying , Carozzi Valentina A. , Rodriguez-Menendez Virginia , Ballarini Elisa , Alberti Paola , Pozzi Eleonora , Semperboni Sara , Cook Brett M. , Littlefield Bruce A. , Nomoto Kenichi , Condon Krista , Eckley Sean , DesJardins Christopher , Wilson Leslie , Jordan Mary A. , Feinstein Stuart C. , Cavaletti Guido , Polydefkis Michael , Slusher Barbara S.
Published: March 2023

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of disability in cancer survivors. CIPN investigations in preclinical model systems have focused on either behaviors or acute changes in nerve conduction velocity (NCV) and amplitude, but greater understanding of the underlying nature of axonal injury and its long-term processes is needed as cancer patients live longer. In this study, we used multiple independent endpoints to systematically characterize CIPN recovery in mice exposed to the antitubulin cancer drugs eribulin, ixabepilone, paclitaxel, or vinorelbine at MTDs. All of the drugs ablated intraepidermal nerve fibers and produced axonopathy, with a secondary disruption in myelin structure within 2 weeks of drug administration. In addition, all of the drugs reduced sensory NCV and amplitude, with greater deficits after paclitaxel and lesser deficits after ixabepilone. These effects correlated with degeneration in dorsal root ganglia (DRG) and sciatic nerve and abundance of Schwann cells. Although most injuries were fully reversible after 3–6 months after administration of eribulin, vinorelbine, and ixabepilone, we observed delayed recovery after paclitaxel that produced a more severe, pervasive, and prolonged neurotoxicity. Compared with other agents, paclitaxel also displayed a unique prolonged exposure in sciatic nerve and DRG. The most sensitive indicator of toxicity was axonopathy and secondary myelin changes accompanied by a reduction in intraepidermal nerve fiber density. Taken together, our findings suggest that intraepidermal nerve fiber density and changes in NCV and amplitude might provide measures of axonal injury to guide clinical practice.

Significance: This detailed preclinical study of the long-term effects of widely used antitubulin cancer drugs on the peripheral nervous system may help guide clinical evaluations to improve personalized care in limiting neurotoxicity in cancer survivors. Cancer Res; 78(3); 817–29. ©2017 AACR.
Data from Synthetic Lethality of PARP Inhibitors in Combination with MYC Blockade Is Independent of BRCA Status in Triple-Negative Breast Cancer
Authors: Carey Jason. P.W. , Karakas Cansu , Bui Tuyen , Chen Xian , Vijayaraghavan Smruthi , Zhao Yang , Wang Jing , Mikule Keith , Litton Jennifer K. , Hunt Kelly K. , Keyomarsi Khandan
Published: March 2023

Abstract
PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients. Several of those patients exhibit intrinsic/acquired resistance mechanisms that limit efficacy of PARPi monotherapy. Here we show how the efficacy of PARPi in triple-negative breast cancers (TNBC) can be expanded by targeting MYC-induced oncogenic addiction. In BRCA-mutant/sporadic TNBC patients, amplification of the MYC gene is correlated with increased expression of the homologous DNA recombination enzyme RAD51 and tumors overexpressing both genes are associated with worse overall survival. Combining MYC blockade with PARPi yielded synthetic lethality in MYC-driven TNBC cells. Using the cyclin-dependent kinase inhibitor dinaciclib, which downregulates MYC expression, we found that combination with the PARPi niraparib increased DNA damage and downregulated homologous recombination, leading to subsequent downregulation of the epithelial–mesenchymal transition and cancer stem-like cell phenotypes. Notably, dinaciclib resensitized TBNC cells, which had acquired resistance to niraparib. We found that the synthetic lethal strategy employing dinaciclib and niraparib was also highly efficacious in ovarian, prostate, pancreatic, colon, and lung cancer cells. Taken together, our results show how blunting MYC oncogene addiction can leverage cancer cell sensitivity to PARPi, facilitating the clinical use of c-myc as a predictive biomarker for this treatment.

Significance: Dual targeting of MYC-regulated homologous recombination and PARP-mediated DNA repair yields potent synthetic lethality in triple-negative breast tumors and other aggressive tumors characterized by MYC overexpression. Cancer Res; 78(3); 742–57. ©2017 AACR.
Data from Multikinase Inhibitor CT-707 Targets Liver Cancer by Interrupting the Hypoxia-Activated IGF-1R–YAP Axis
Authors: Zhu Hong , Wang Dan-Dan , Yuan Tao , Yan Fang-Jie , Zeng Chen-Ming , Dai Xiao-Yang , Chen Zi-bo , Chen Ying , Zhou Tianyi , Fan Guang-Han , Ying Meidan , Cao Ji , Luo Peihua , Liu Xi-Jie , Hu Yuandong , Peng Yong , He Qiaojun , Yang Bo
Published: March 2023

Abstract
Given that Yes-associated protein (YAP) signaling acts as a critical survival input for hypoxic cancer cells in hepatocellular carcinoma (HCC), disruption of YAP function and the maintenance of hypoxia is an attractive way to treat HCC. Utilizing a cell-based YAP-TEAD luciferase reporter assay and functional analyses, we identified CT-707, a China-FDA approved multi-kinase inhibitor under clinical trial with remarkable inhibitory activity against YAP function. CT-707 exhibited prominent cytotoxicity under hypoxia on HCC cells, which was attributable to the inhibition of YAP signaling. CT-707 arrested tumor growth in HepG2, Bel-7402, and HCC patient-derived xenografts. Mechanistically, the inhibitory activity of CT-707 on YAP signaling was due to the interruption of hypoxia-activated IGF1R. Overall, these findings not only identify CT-707 as a promising hypoxia-targeting agent against HCC, but they also unveil IGF1R as a new modulator specifically regulating hypoxia-activated YAP signaling.

Significance: CT-707 may represent a novel clinical approach for patients with HCC suffering poor drug response due to intratumor hypoxia. Cancer Res; 78(14); 3995–4006. ©2018 AACR.
Data from PPARδ Elicits Ligand-Independent Repression of Trefoil Factor Family to Limit Prostate Cancer Growth
Authors: Martín-Martín Natalia , Zabala-Letona Amaia , Fernández-Ruiz Sonia , Arreal Leire , Camacho Laura , Castillo-Martin Mireia , Cortazar Ana R. , Torrano Verónica , Astobiza Ianire , Zúñiga-García Patricia , Ugalde-Olano Aitziber , Loizaga-Iriarte Ana , Unda Miguel , Valcárcel-Jiménez Lorea , Arruabarrena-Aristorena Amaia , Piva Marco , Sánchez-Mosquera Pilar , Aransay Ana M. , Gomez-Muñoz Antonio , Barrio Rosa , Sutherland James D. , Carracedo Arkaitz
Published: March 2023

Abstract
The nuclear receptor PPAR-β/δ (PPARD) has essential roles in fatty acid catabolism and energy homeostasis as well as cell differentiation, inflammation, and metabolism. However, its contributions to tumorigenesis are uncertain and have been disputed. Here, we provide evidence of tumor suppressive activity of PPARD in prostate cancer through a noncanonical and ligand-independent pathway. PPARD was downregulated in prostate cancer specimens. In murine prostate epithelium, PPARD gene deletion resulted in increased cellularity. Genetic modulation of PPARD in human prostate cancer cell lines validated the tumor suppressive activity of this gene in vitro and in vivo. Mechanistically, PPARD exerted its activity in a DNA binding-dependent and ligand-independent manner. We identified a novel set of genes repressed by PPARD that failed to respond to ligand-mediated activation. Among these genes, we observed robust regulation of the secretory trefoil factor family (TFF) members, including a causal and correlative association of TFF1 with prostate cancer biology in vitro and in patient specimens. Overall, our results illuminate the oncosuppressive function of PPARD and understanding of the pathogenic molecular pathways elicited by this nuclear receptor.

Significance: These findings challenge the presumption that the function of the nuclear receptor PPARβ/δ in cancer is dictated by ligand-mediated activation. Cancer Res; 78(2); 399–409. ©2017 AACR.
Data from Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis
Authors: Wu Yanming , Zhang Zhao , Cenciarini Mauro E. , Proietti Cecilia J. , Amasino Matias , Hong Tao , Yang Mei , Liao Yiji , Chiang Huai-Chin , Kaklamani Virginia G. , Jeselsohn Rinath , Vadlamudi Ratna K. , Huang Tim Hui-Ming , Li Rong , De Angelis Carmine , Fu Xiaoyong , Elizalde Patricia V. , Schiff Rachel , Brown Myles , Xu Kexin
Published: March 2023

Abstract
Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.

Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671–84. ©2017 AACR.
Data from Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Resensitization to Platinum Drugs
Authors: Fang Fang , Cardenas Horacio , Huang Hao , Jiang Guanglong , Perkins Susan M. , Zhang Chi , Keer Harold N. , Liu Yunlong , Nephew Kenneth P. , Matei Daniela
Published: March 2023

Abstract
DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer. In this study, we elucidated an epigenetic signature associated with platinum drug resensitization that may offer utility in predicting the outcomes of patients who are coadministered a DNA methyltransferase inhibitor. The ovarian cancer specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant ovarian cancer who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard-of-care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1,659 genes differentially expressed in pretreatment versus posttreatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune reactivation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1,155 genes involved in 25 networks. In functional investigations in ovarian cancer cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-193a, and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize ovarian cancer cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of ovarian cancer patients.

Significance: Epigenomic targeting may improve therapeutic outcomes in platinum-resistant and recurrent ovarian cancer in part by effects on DNA repair and antitumor immune responses. Cancer Res; 78(3); 631–44. ©2017 AACR.
Data from MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL
Authors: Zhou Mi , Zhou Kuangguo , Cheng Ling , Chen Xing , Wang Jue , Wang Xiao-Min , Zhang Yingchi , Yu Qilin , Zhang Shu , Wang Di , Huang Liang , Huang Mei , Ma Ding , Cheng Tao , Wang Cong-Yi , Yuan Weiping , Zhou Jianfeng
Published: March 2023

Abstract
Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after in vivo reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T-cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway. In clinical specimens of human T-ALL, Wnt signaling pathway signatures were significantly enhanced and positively correlated with the expression and function of MBD2. Furthermore, a number of typical Wnt signaling inhibitory genes were abnormally hypermethylated in primary human T-ALL. Abnormal activation of Wnt signaling in T-ALL was switched off by MBD2 deletion, partially by reactivating epigenetically silenced Wnt signaling inhibitors. Taken together, our results define essential roles for MBD2 in lymphopoiesis and T-ALL and suggest MBD2 as a candidate therapeutic target in T-ALL.

Significance: This study highlights a methylated DNA binding protein as a candidate therapeutic target to improve the treatment of T-cell acute lymphoblastic leukemias, as a new starting point for developing epigenetic therapy in this and other lymphoid malignancies. Cancer Res; 78(7); 1632–42. ©2018 AACR.
Data from Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition
Authors: Ishizawa Jo , Nakamaru Kenji , Seki Takahiko , Tazaki Koichi , Kojima Kensuke , Chachad Dhruv , Zhao Ran , Heese Lauren , Ma Wencai , Ma Man Chun John , DiNardo Courtney , Pierce Sherry , Patel Keyur P. , Tse Archie , Davis R. Eric , Rao Arvind , Andreeff Michael
Published: March 2023

Abstract
Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells; however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b. However, sensitivity to DS-3032b of TP53 wild-type tumors varied greatly. We thus used two methods to create predictive gene signatures. First, by comparing sensitivity to MDM2 inhibition with basal mRNA expression profiles in 240 cancer cell lines, a 175-gene signature was defined and validated in patient-derived tumor xenograft models and ex vivo human acute myeloid leukemia (AML) cells. Second, an AML-specific 1,532-gene signature was defined by performing random forest analysis with cross-validation using gene expression profiles of 41 primary AML samples. The combination of TP53 mutation status with the two gene signatures provided the best positive predictive values (81% and 82%, compared with 62% for TP53 mutation status alone). In addition, the top-ranked 50 genes selected from the AML-specific 1,532-gene signature conserved high predictive performance, suggesting that a more feasible size of gene signature can be generated through this method for clinical implementation. Our model is being tested in ongoing clinical trials of MDM2 inhibitors.

Significance: This study demonstrates that gene expression profiling combined with TP53 mutational status predicts antitumor effects of MDM2 inhibitors in vitro and in vivo. Cancer Res; 78(10); 2721–31. ©2018 AACR.
Data from hPCL3s Promotes Hepatocellular Carcinoma Metastasis by Activating β-Catenin Signaling
Authors: Cai Zhen , Qian Zhen-Yu , Jiang Hao , Ma Ning , Li Zhi , Liu Li-Yu , Ren Xin-Xin , Shang Yu-Rong , Wang Jing-Jing , Li Jing-Jing , Liu Dong-Ping , Zhang Xiu-Ping , Feng Dan , Ni Qian-Zhi , Feng Yuan-Yuan , Li Nan , Zhou Xiao-Yan , Wang Xiang , Bao Ying , Zhang Xue-Li , Deng Yue-Zhen , Xie Dong
Published: March 2023

Abstract
Two isoforms of human Polycomb-like protein 3 (hPCL3) have been reported as components of the nuclear Polycomb repressive complex 2 (PRC2), with the short isoform (hPCL3s) showing a dominant cytoplasmic localization. The function of cytoplasmic hPCL3s has, however, not been addressed. In this study, we report that hPCL3s is upregulated in clinical hepatocellular carcinoma (HCC) samples and its expression correlated with HCC clinical features. hPCL3s positively regulated the migration, invasion, and metastasis of HCC cells. hPCL3s interacted with components of the cytoplasmic β-catenin destruction complex, inhibited β-catenin degradation, and activated β-catenin/T-cell factor signaling. Downstream of the β-catenin cascade, IL6 mediated the motility-promoting functions of hPCL3s. Forced expression of hPCL3s in the liver of a HCC mouse model promoted tumorigenesis and metastasis. Taken together, these data show that hPCL3s promotes the metastasis of HCC by activating the β-catenin/IL6 pathway.

Significance: hPCL3s has an oncogenic role in hepatocellular carcinoma by activating the β-catenin/IL6 signaling axis to promote metastasis. Cancer Res; 78(10); 2536–49. ©2018 AACR.
Data from Membrane-Depolarizing Channel Blockers Induce Selective Glioma Cell Death by Impairing Nutrient Transport and Unfolded Protein/Amino Acid Responses
Authors: Niklasson Mia , Maddalo Gianluca , Sramkova Zuzana , Mutlu Ercan , Wee Shimei , Sekyrova Petra , Schmidt Linnéa , Fritz Nicolas , Dehnisch Ivar , Kyriatzis Gregorios , Krafcikova Michaela , Carson Brittany B. , Feenstra Jennifer M. , Marinescu Voichita D. , Segerman Anna , Haraldsson Martin , Gustavsson Anna-Lena , Hammarström Lars G.J. , Jenmalm Jensen Annika , Uhrbom Lene , Altelaar A.F. Maarten , Linnarsson Sten , Uhlén Per , Trantirek Lukas , Vincent C. Theresa , Nelander Sven , Enger Per Øyvind , Andäng Michael
Published: March 2023

Abstract
Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown. However, using cell-based assays and integrated proteomics, phosphoproteomics, and transcriptomics analyses, we identified the downstream signaling events these drugs affect. Changes in plasma membrane depolarization and elevated intracellular Na+, which compromised Na+-dependent nutrient transport, were documented. Deficits in nutrient deficit acted in turn to trigger the unfolded protein response and the amino acid response, leading ultimately to nutrient starvation and GIC cell death. Our results suggest new therapeutic targets to attack aggressive gliomas. Cancer Res; 77(7); 1741–52. ©2017 AACR.
Data from E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C
Authors: Chen Xiaohua , Loo Jun Xian , Shi Xin , Xiong Wenjun , Guo Yong , Ke Haiqiang , Yang Mingkun , Jiang Yanping , Xia Siyu , Zhao Min , Zhong Shan , He Chunjiang , Fu Li , Li Feng
Published: March 2023

Abstract
The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.

Significance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. Cancer Res; 78(6); 1418–30. ©2018 AACR.
Data from Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF
Authors: Shao Wenlin , Mishina Yuji M. , Feng Yun , Caponigro Giordano , Cooke Vesselina G. , Rivera Stacy , Wang Yingyun , Shen Fang , Korn Joshua M. , Mathews Griner Lesley A. , Nishiguchi Gisele , Rico Alice , Tellew John , Haling Jacob R. , Aversa Robert , Polyakov Valery , Zang Richard , Hekmat-Nejad Mohammad , Amiri Payman , Singh Mallika , Keen Nicholas , Dillon Michael P. , Lees Emma , Ramurthy Savithri , Sellers William R. , Stuart Darrin D.
Published: March 2023

Abstract
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor–derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.

Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537–48. ©2018 AACR.
Data from Tight Junction Protein Claudin-2 Promotes Self-Renewal of Human Colorectal Cancer Stem-like Cells
Authors: Paquet-Fifield Sophie , Koh Shir Lin , Cheng Lesley , Beyit Laura M. , Shembrey Carolyn , Mølck Christina , Behrenbruch Corina , Papin Marina , Gironella Meritxell , Guelfi Sophie , Nasr Ramona , Grillet Fanny , Prudhomme Michel , Bourgaux Jean-Francois , Castells Antoni , Pascussi Jean-Marc , Heriot Alexander G. , Puisieux Alain , Davis Melissa J. , Pannequin Julie , Hill Andrew F. , Sloan Erica K. , Hollande Frédéric
Published: March 2023

Abstract
Posttreatment recurrence of colorectal cancer, the third most lethal cancer worldwide, is often driven by a subpopulation of cancer stem cells (CSC). The tight junction (TJ) protein claudin-2 is overexpressed in human colorectal cancer, where it enhances cell proliferation, colony formation, and chemoresistance in vitro. While several of these biological processes are features of the CSC phenotype, a role for claudin-2 in the regulation of these has not been identified. Here, we report that elevated claudin-2 expression in stage II/III colorectal tumors is associated with poor recurrence-free survival following 5-fluorouracil–based chemotherapy, an outcome in which CSCs play an instrumental role. In patient-derived organoids, primary cells, and cell lines, claudin-2 promoted colorectal cancer self-renewal in vitro and in multiple mouse xenograft models. Claudin-2 enhanced self-renewal of ALDHHigh CSCs and increased their proportion in colorectal cancer cell populations, limiting their differentiation and promoting the phenotypic transition of non-CSCs toward the ALDHHigh phenotype. Next-generation sequencing in ALDHHigh cells revealed that claudin-2 regulated expression of nine miRNAs known to control stem cell signaling. Among these, miR-222-3p was instrumental for the regulation of self-renewal by claudin-2, and enhancement of this self-renewal required activation of YAP, most likely upstream from miR-222-3p. Taken together, our results indicate that overexpression of claudin-2 promotes self-renewal within colorectal cancer stem-like cells, suggesting a potential role for this protein as a therapeutic target in colorectal cancer.

Significance: Claudin-2-mediated regulation of YAP activity and miR-222-3p expression drives CSC renewal in colorectal cancer, making it a potential target for therapy. Cancer Res; 78(11); 2925–38. ©2018 AACR.
Data from Histone Acetyltransferase Activity of MOF Is Required for MLL-AF9 Leukemogenesis
Authors: Valerio Daria G. , Xu Haiming , Chen Chun-Wei , Hoshii Takayuki , Eisold Meghan E. , Delaney Christopher , Cusan Monica , Deshpande Aniruddha J. , Huang Chun-Hao , Lujambio Amaia , Zheng YuJun George , Zuber Johannes , Pandita Tej K. , Lowe Scott W. , Armstrong Scott A.
Published: March 2023

Abstract
Chromatin-based mechanisms offer therapeutic targets in acute myeloid leukemia (AML) that are of great current interest. In this study, we conducted an RNAi-based screen to identify druggable chromatin regulator–based targets in leukemias marked by oncogenic rearrangements of the MLL gene. In this manner, we discovered the H4K16 histone acetyltransferase (HAT) MOF to be important for leukemia cell growth. Conditional deletion of Mof in a mouse model of MLL-AF9–driven leukemogenesis reduced tumor burden and prolonged host survival. RNA sequencing showed an expected downregulation of genes within DNA damage repair pathways that are controlled by MOF, as correlated with a significant increase in yH2AX nuclear foci in Mof-deficient MLL-AF9 tumor cells. In parallel, Mof loss also impaired global H4K16 acetylation in the tumor cell genome. Rescue experiments with catalytically inactive mutants of MOF showed that its enzymatic activity was required to maintain cancer pathogenicity. In support of the role of MOF in sustaining H4K16 acetylation, a small-molecule inhibitor of the HAT component MYST blocked the growth of both murine and human MLL-AF9 leukemia cell lines. Furthermore, Mof inactivation suppressed leukemia development in an NUP98-HOXA9–driven AML model. Taken together, our results establish that the HAT activity of MOF is required to sustain MLL-AF9 leukemia and may be important for multiple AML subtypes. Blocking this activity is sufficient to stimulate DNA damage, offering a rationale to pursue MOF inhibitors as a targeted approach to treat MLL-rearranged leukemias. Cancer Res; 77(7); 1753–62. ©2017 AACR.
Data from Adaptive Evolution of the GDH2 Allosteric Domain Promotes Gliomagenesis by Resolving IDH1R132H-Induced Metabolic Liabilities
Authors: Waitkus Matthew S. , Pirozzi Christopher J. , Moure Casey J. , Diplas Bill H. , Hansen Landon J. , Carpenter Austin B. , Yang Rui , Wang Zhaohui , Ingram Brian O. , Karoly Edward D. , Mohney Robert P. , Spasojevic Ivan , McLendon Roger E. , Friedman Henry S. , He Yiping , Bigner Darell D. , Yan Hai
Published: March 2023

Abstract
Hotspot mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in a number of human cancers and confer a neomorphic enzyme activity that catalyzes the conversion of α-ketoglutarate (αKG) to the oncometabolite D-(2)-hydroxyglutarate (D2HG). In malignant gliomas, IDH1R132H expression induces widespread metabolic reprogramming, possibly requiring compensatory mechanisms to sustain the normal biosynthetic requirements of actively proliferating tumor cells. We used genetically engineered mouse models of glioma and quantitative metabolomics to investigate IDH1R132H-dependent metabolic reprogramming and its potential to induce biosynthetic liabilities that can be exploited for glioma therapy. In gliomagenic neural progenitor cells, IDH1R132H expression increased the abundance of dipeptide metabolites, depleted key tricarboxylic acid cycle metabolites, and slowed progression of murine gliomas. Notably, expression of glutamate dehydrogenase GDH2, a hominoid-specific enzyme with relatively restricted expression to the brain, was critically involved in compensating for IDH1R132H-induced metabolic alterations and promoting IDH1R132H glioma growth. Indeed, we found that recently evolved amino acid substitutions in the GDH2 allosteric domain conferred its nonredundant, glioma-promoting properties in the presence of IDH1 mutation. Our results indicate that among the unique roles for GDH2 in the human forebrain is its ability to limit IDH1R132H-mediated metabolic liabilities, thus promoting glioma growth in this context. Results from this study raise the possibility that GDH2-specific inhibition may be a viable therapeutic strategy for gliomas with IDH mutations.

Significance: These findings show that the homonid-specific brain enzyme GDH2 may be essential to mitigate metabolic liabilities created by IDH1 mutations in glioma, with possible implications to leverage its therapeutic management by IDH1 inhibitors. Cancer Res; 78(1); 36–50. ©2017 AACR.
Data from Organelle-Derived Acetyl-CoA Promotes Prostate Cancer Cell Survival, Migration, and Metastasis via Activation of Calmodulin Kinase II
Authors: Yu Guoyu , Cheng Chien-Jui , Lin Song-Chang , Lee Yu-Chen , Frigo Daniel E. , Yu-Lee Li-Yuan , Gallick Gary E. , Titus Mark A. , Nutt Leta K. , Lin Sue-Hwa
Published: March 2023

Abstract
Although emerging evidence suggests a potential role of calcium/calmodulin-dependent kinase II (CaMKII) in prostate cancer, its role in prostate cancer tumorigenesis is largely unknown. Here, we examine whether the acetyl CoA-CaMKII pathway, first described in frog oocytes, promotes prostate cancer tumorigenesis. In human prostate cancer specimens, metastatic prostate cancer expressed higher levels of active CaMKII compared with localized prostate cancer. Correspondingly, basal CaMKII activity was significantly higher in the more tumorigenic PC3 and PC3-mm2 cells relative to the less tumorigenic LNCaP and C4-2B4 cells. Deletion of CaMKII by CRISPR/Cas9 in PC3-mm2 cells abrogated cell survival under low-serum conditions, anchorage-independent growth and cell migration; overexpression of constitutively active CaMKII in C4-2B4 cells promoted these phenotypes. In an animal model of prostate cancer metastasis, genetic ablation of CaMKII reduced PC3-mm2 cell metastasis from the prostate to the lymph nodes. Knockdown of the acetyl-CoA transporter carnitine acetyltransferase abolished CaMKII activation, providing evidence that acetyl-CoA generated from organelles is a major activator of CaMKII. Genetic deletion of the β-oxidation rate-limiting enzyme ACOX family proteins decreased CaMKII activation, whereas overexpression of ACOXI increased CaMKII activation. Overall, our studies identify active CaMKII as a novel connection between organelle β-oxidation and acetyl-CoA transport with cell survival, migration, and prostate cancer metastasis.

Significance: This study identifies a cell metabolic pathway that promotes prostate cancer metastasis and suggests prostate cancer may be susceptible to β-oxidation inhibitors. Cancer Res; 78(10); 2490–502. ©2018 AACR.
Data from Tumor–Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer
Authors: Zhang Daoxiang , Li Lin , Jiang Hongmei , Li Qiong , Wang-Gillam Andrea , Yu Jinsheng , Head Richard , Liu Jingxia , Ruzinova Marianna B. , Lim Kian-Huat
Published: March 2023

Abstract
Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor–associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor–stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.

Significance: Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. Cancer Res; 78(7); 1700–12. ©2018 AACR.
Data from Breast Cancer Targeting through Inhibition of the Endoplasmic Reticulum-Based Apoptosis Regulator Nrh/BCL2L10
Authors: Nougarede Adrien , Popgeorgiev Nikolay , Kassem Loay , Omarjee Soleilmane , Borel Stephane , Mikaelian Ivan , Lopez Jonathan , Gadet Rudy , Marcillat Olivier , Treilleux Isabelle , Villoutreix Bruno O. , Rimokh Ruth , Gillet Germain
Published: March 2023

Abstract
Drug resistance and metastatic relapse remain a top challenge in breast cancer treatment. In this study, we present preclinical evidence for a strategy to eradicate advanced breast cancers by targeting the BCL-2 homolog Nrh/BCL2L10, which we discovered to be overexpressed in >45% of a large cohort of breast invasive carcinomas. Nrh expression in these tumors correlated with reduced metastasis-free survival, and we determined it to be an independent marker of poor prognosis. Nrh protein localized to the endoplasmic reticulum. Mechanistic investigations showed that Nrh made BH4 domain–dependent interactions with the ligand-binding domain of the inositol-1,4,5-triphosphate receptor (IP3R), a type 1/3 Ca2+ channel, allowing Nrh to negatively regulate ER-Ca2+ release and to mediate antiapoptosis. Notably, disrupting Nrh/IP3R complexes by BH4 mimetic peptides was sufficient to inhibit the growth of breast cancer cells in vitro and in vivo. Taken together, our results highlighted Nrh as a novel prognostic marker and a candidate therapeutic target for late stage breast cancers that may be addicted to Nrh.

Significance: These findings offer a comprehensive molecular model for the activity of Nrh/BCL2L10, a little studied antiapoptotic molecule, prognostic marker, and candidate drug target in breast cancer. Cancer Res; 78(6); 1404–17. ©2018 AACR.
Data from Genetic Hitchhiking and Population Bottlenecks Contribute to Prostate Cancer Disparities in Men of African Descent
Authors: Lachance Joseph , Berens Ali J. , Hansen Matthew E.B. , Teng Andrew K. , Tishkoff Sarah A. , Rebbeck Timothy R.
Published: March 2023

Abstract
Prostate cancer incidence and mortality rates in African and African American men are greatly elevated compared with other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to prostate cancer disparities is unclear. Here, we investigated the population structure of 68 previously reported GWAS loci and calculated genetic disparity contribution statistics to identify SNPs that contribute the most to differences in prostate cancer risk across populations. By integrating GWAS results with allele frequency data, we generated genetic risk scores for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of prostate cancer risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated prostate cancer risks in men of African descent, including rs9623117, rs6983267, rs10896449, rs10993994, and rs817826. Although most prostate cancer–associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of prostate cancer in African and African American men.

Significance: A small number of genetic variants cause an elevated risk of prostate cancer in men of West African descent. Cancer Res; 78(9); 2432–43. ©2018 AACR.
Data from Human Elongation Factor 4 Regulates Cancer Bioenergetics by Acting as a Mitochondrial Translation Switch
Authors: Zhu Ping , Liu Yongzhang , Zhang Fenglin , Bai Xiufeng , Chen Zilei , Shangguan Fugen , Zhang Bo , Zhang Lingyun , Chen Qianqian , Xie Deyao , Lan Linhua , Xue Xiangdong , Liang Xing-Jie , Lu Bin , Wei Taotao , Qin Yan
Published: March 2023

Abstract
Mitochondria regulate cellular bioenergetics and redox states and influence multiple signaling pathways required for tumorigenesis. In this study, we determined that the mitochondrial translation elongation factor 4 (EF4) is a critical component of tumor progression. EF4 was ubiquitous in human tissues with localization to the mitochondria (mtEF4) and performed quality control on respiratory chain biogenesis. Knockout of mtEF4 induced respiratory chain complex defects and apoptosis, while its overexpression stimulated cancer development. In multiple cancers, expression of mtEF4 was increased in patient tumor tissues. These findings reveal that mtEF4 expression may promote tumorigenesis via an imbalance in the regulation of mitochondrial activities and subsequent variation of cellular redox. Thus, dysregulated mitochondrial translation may play a vital role in the etiology and development of diverse human cancers.

Significance: Dysregulated mitochondrial translation drives tumor development and progression. Cancer Res; 78(11); 2813–24. ©2018 AACR.
Data from microRNA-1246 Is an Exosomal Biomarker for Aggressive Prostate Cancer
Authors: Bhagirath Divya , Yang Thao Ly , Bucay Nathan , Sekhon Kirandeep , Majid Shahana , Shahryari Varahram , Dahiya Rajvir , Tanaka Yuichiro , Saini Sharanjot
Published: March 2023

Abstract
Because of high heterogeneity, molecular characterization of prostate cancer based on biopsy sampling is often challenging. Hence, a minimally invasive method to determine the molecular imprints of a patient's tumor for risk stratification would be advantageous. In this study, we employ a novel, digital amplification-free quantification method using the nCounter technology (NanoString Technologies) to profile exosomal serum miRNAs (ex-miRNA) from aggressive prostate cancer cases, benign prostatic hyperplasia, and disease-free controls. We identified several dysregulated miRNAs, one of which was the tumor suppressor miR-1246. miR-1246 was downregulated in prostate cancer clinical tissues and cell lines and was selectively released into exosomes. Overexpression of miR-1246 in a prostate cancer cell line significantly inhibited xenograft tumor growth in vivo and increased apoptosis and decreased proliferation, invasiveness, and migration in vitro. miR-1246 inhibited N-cadherin and vimentin activities, thereby inhibiting epithelial–mesenchymal transition. Ex-miR-1246 expression correlated with increasing pathologic grade, positive metastasis, and poor prognosis. Our analyses suggest ex-miR-1246 as a promising prostate cancer biomarker with diagnostic potential that can predict disease aggressiveness.

Significance: Dysregulation of exosomal miRNAs in aggressive prostate cancer leads to alteration of key signaling pathways associated with metastatic prostate cancer. Cancer Res; 78(7); 1833–44. ©2018 AACR.
Data from ER Stress Signaling Promotes the Survival of Cancer “Persister Cells” Tolerant to EGFR Tyrosine Kinase Inhibitors
Authors: Terai Hideki , Kitajima Shunsuke , Potter Danielle S. , Matsui Yusuke , Quiceno Laura Gutierrez , Chen Ting , Kim Tae-jung , Rusan Maria , Thai Tran C. , Piccioni Federica , Donovan Katherine A. , Kwiatkowski Nicholas , Hinohara Kunihiko , Wei Guo , Gray Nathanael S. , Fischer Eric S. , Wong Kwok-Kin , Shimamura Teppei , Letai Anthony , Hammerman Peter S. , Barbie David A.
Published: March 2023

Abstract
An increasingly recognized component of resistance to tyrosine kinase inhibitors (TKI) involves persistence of a drug-tolerant subpopulation of cancer cells that survive despite effective eradication of the majority of the cell population. Multiple groups have demonstrated that these drug-tolerant persister cells undergo transcriptional adaptation via an epigenetic state change that promotes cell survival. Because this mode of TKI drug tolerance appears to involve transcriptional addiction to specific genes and pathways, we hypothesized that systematic functional screening of EGFR TKI/transcriptional inhibitor combination therapy would yield important mechanistic insights and alternative drug escape pathways. We therefore performed a genome-wide CRISPR/Cas9 enhancer/suppressor screen in EGFR-dependent lung cancer PC9 cells treated with erlotinib + THZ1 (CDK7/12 inhibitor) combination therapy, a combination previously shown to suppress drug-tolerant cells in this setting. As expected, suppression of multiple genes associated with transcriptional complexes (EP300, CREBBP, and MED1) enhanced erlotinib/THZ1 synergy. Unexpectedly, we uncovered nearly every component of the recently described ufmylation pathway in the synergy suppressor group. Loss of ufmylation did not affect canonical downstream EGFR signaling. Instead, absence of this pathway triggered a protective unfolded protein response associated with STING upregulation, promoting protumorigenic inflammatory signaling but also unique dependence on Bcl-xL. These data reveal that dysregulation of ufmylation and ER stress comprise a previously unrecognized TKI drug tolerance pathway that engages survival signaling, with potentially important therapeutic implications.

Significance: These findings reveal a novel function of the recently described ufmylation pathway, an ER stress survival signaling in drug-tolerant persister cells, which has important biological and therapeutic implications. Cancer Res; 78(4); 1044–57. ©2017 AACR.