bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention
Authors: Ingle James N. , Liu Mohan , Wickerham D. Lawrence , Schaid Daniel J. , Wang Liewei , Mushiroda Taisei , Kubo Michiaki , Costantino Joseph P. , Vogel Victor G. , Paik Soonmyung , Goetz Matthew P. , Ames Matthew M. , Jenkins Gregory D. , Batzler Anthony , Carlson Erin E. , Flockhart David A. , Wolmark Norman , Nakamura Yusuke , Weinshilboum Richard M.
Published: March 2024

Abstract
The selective estrogen receptor modulators (SERM) tamoxifen and raloxifene can reduce the occurrence of breast cancer in high-risk women by 50%, but this U.S. Food and Drug Administration-approved prevention therapy is not often used. We attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention, using DNA from the NSABP P-1 and P-2 breast cancer prevention trials. An initial discovery genome-wide association study identified common single-nucleotide polymorphisms (SNP) in or near the ZNF423 and CTSO genes that were associated with breast cancer risk during SERM therapy. We then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor. The OR for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71.

Significance: This study identified novel, functionally polymorphic genes involved in the estrogen-dependent regulation of BRCA1 expression, as well as a novel mechanism for genetic variation in SERM therapeutic effect. These observations, and definition of their underlying mechanisms, represent steps toward pharmacogenomically individualized SERM breast cancer prevention. Cancer Discov; 3(7); 812–25. ©2013 AACR.

See related commentary by Machiela and Chanock, p. 728

This article is highlighted in the In This Issue feature, p. 705
Data from The Genetics of Splicing in Neuroblastoma
Authors: Chen Justin , Hackett Christopher S. , Zhang Shile , Song Young K. , Bell Robert J.A. , Molinaro Annette M. , Quigley David A. , Balmain Allan , Song Jun S. , Costello Joseph F. , Gustafson W. Clay , Van Dyke Terry , Kwok Pui-Yan , Khan Javed , Weiss William A.
Published: March 2024

Abstract
Regulation of mRNA splicing, a critical and tightly regulated cellular function, underlies the majority of proteomic diversity and is frequently disrupted in disease. Using an integrative genomics approach, we combined both genomic data and exon-level transcriptome data in two somatic tissues (cerebella and peripheral ganglia) from a transgenic mouse model of neuroblastoma, a tumor that arises from the peripheral neural crest. Here, we describe splicing quantitative trait loci associated with differential splicing across the genome that we use to identify genes with previously unknown functions within the splicing pathway and to define de novo intronic splicing motifs that influence splicing from hundreds of bases away. Our results show that these splicing motifs represent sites for functional recurrent mutations and highlight novel candidate genes in human cancers, including childhood neuroblastoma.

Significance: Somatic mutations with predictable downstream effects are largely relegated to coding regions, which comprise less than 2% of the human genome. Using an unbiased in vivo analysis of a mouse model of neuroblastoma, we have identified intronic splicing motifs that translate into sites for recurrent somatic mutations in human cancers. Cancer Discov; 5(4); 380–95. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 333
Data from Parallel RNA Interference Screens Identify EGFR Activation as an Escape Mechanism in FGFR3-Mutant Cancer
Authors: Herrera-Abreu Maria Teresa , Pearson Alex , Campbell James , Shnyder Steve D. , Knowles Margaret A. , Ashworth Alan , Turner Nicholas C.
Published: March 2024

Abstract
Activation of fibroblast growth factor receptors (FGFR) is a common oncogenic event. Little is known about the determinants of sensitivity to FGFR inhibition and how these may vary between different oncogenic FGFRs. Using parallel RNA interference (RNAi) genetic screens, we show that the EGF receptor (EGFR) limits sensitivity to FGFR inhibition in FGFR3-mutant and -translocated cell lines, but not in other FGFR-driven cell lines. We also identify two distinct mechanisms through which EGFR limits sensitivity. In partially FGFR3-dependent lines, inhibition of FGFR3 results in transient downregulation of mitogen-activated protein kinase signaling that is rescued by rapid upregulation of EGFR signaling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signaling via repression of FGFR3, with EGFR inhibition rescued by delayed upregulation of FGFR3 expression. Importantly, combinations of FGFR and EGFR inhibitors overcome these resistance mechanisms in vitro and in vivo. Our results illustrate the power of parallel RNAi screens in identifying common resistance mechanisms to targeted therapies.

Significance: Our data identify a novel therapeutic approach to the treatment of FGFR3-mutant cancer, emphasizing the potential of combination approaches targeting both FGFR3 and EGFR. Our data extend the role of EGFR in mediating resistance to inhibitors targeting a mutant oncogene, showing that EGFR signaling can repress mutant FGFR3 to induce intrinsic resistance to FGFR targeting. Cancer Discov; 3(9); 1058–71. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 953
Data from mTOR Inhibition Specifically Sensitizes Colorectal Cancers with KRAS or BRAF Mutations to BCL-2/BCL-XL Inhibition by Suppressing MCL-1
Authors: Faber Anthony C. , Coffee Erin M. , Costa Carlotta , Dastur Anahita , Ebi Hiromichi , Hata Aaron N. , Yeo Alan T. , Edelman Elena J. , Song Youngchul , Tam Ah Ting , Boisvert Jessica L. , Milano Randy J. , Roper Jatin , Kodack David P. , Jain Rakesh K. , Corcoran Ryan B. , Rivera Miguel N. , Ramaswamy Sridhar , Hung Kenneth E. , Benes Cyril H. , Engelman Jeffrey A.
Published: March 2024

Abstract
Colorectal cancers harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that targets the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS- and BRAF-mutant but not wild-type (WT) colorectal cancer cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not WT, colorectal cancers, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS-mutant colorectal cancer xenograft and genetically engineered mouse models of colorectal cancer, but not in the corresponding KRAS-WT colorectal cancer models. These data suggest that the combination of BCL-2/BCL-XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.

Significance: Effective targeted therapies directed against colorectal cancer with activating mutations in KRAS remain elusive. We have leveraged drug-screen data from a large panel of human colorectal cancers to uncover an effective, rational targeted therapy strategy that has preferential activity in colorectal cancers with KRAS or BRAF mutations. This combination may be developed for clinical testing. Cancer Discov; 4(1); 42–52. ©2013 AACR.

See related commentary by Russo et al., p. 19

This article is highlighted in the In This Issue feature, p. 1
Data from Autophagy Inhibition Improves Chemosensitivity in BRAFV600E Brain Tumors
Authors: Levy Jean M. Mulcahy , Thompson Joshua C. , Griesinger Andrea M. , Amani Vladimir , Donson Andrew M. , Birks Diane K. , Morgan Michael J. , Mirsky David M. , Handler Michael H. , Foreman Nicholas K. , Thorburn Andrew
Published: March 2024

Abstract
Autophagy inhibition is a potential therapeutic strategy in cancer, but it is unknown which tumors will benefit. The BRAFV600E mutation has been identified as important in pediatric central nervous system (CNS) tumors and is known to affect autophagy in other tumor types. We evaluated CNS tumor cells with BRAFV600E and found that mutant (but not wild-type) cells display high rates of induced autophagy, are sensitive to pharmacologic and genetic autophagy inhibition, and display synergy when the clinically used autophagy inhibitor chloroquine was combined with the RAF inhibitor vemurafenib or standard chemotherapeutics. Importantly, we also demonstrate that chloroquine can improve vemurafenib sensitivity in a resistant ex vivo primary culture and provide the first demonstration in a patient harboring the V600E mutation treated with vemurafenib that the addition of chloroquine can improve clinical outcomes. These findings suggest that CNS tumors with BRAFV600E are autophagy-dependent and should be targeted with autophagy inhibition in combination with other therapeutic strategies.

Significance: Autophagy inhibition may improve cancer therapy, but it is unclear which tumors will benefit. We found that BRAF mutations cause brain tumor cells to depend on autophagy and display selective chemosensitization with autophagy inhibition. We present a pediatric case in which deliberate autophagy inhibition halted tumor growth and overcame acquired BRAF-inhibition resistance. Cancer Discov; 4(7); 773–80. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 745
Data from Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment
Authors: Horwitz Elad , Stein Ilan , Andreozzi Mariacarla , Nemeth Julia , Shoham Avivit , Pappo Orit , Schweitzer Nora , Tornillo Luigi , Kanarek Naama , Quagliata Luca , Zreik Farid , Porat Rinnat M. , Finkelstein Rutie , Reuter Hendrik , Koschny Ronald , Ganten Tom , Mogler Carolin , Shibolet Oren , Hess Jochen , Breuhahn Kai , Grunewald Myriam , Schirmacher Peter , Vogel Arndt , Terracciano Luigi , Angel Peter , Ben-Neriah Yinon , Pikarsky Eli
Published: March 2024

Abstract
Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifically in amplicon-positive mouse HCCs. Sorafenib—the first-line drug in advanced HCC—targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA-amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A–blocking drugs.

Significance: Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib—the first-line treatment of advanced HCC—which has an overall moderate therapeutic efficacy. Cancer Discov; 4(6); 730–43. ©2014 AACR.

See related commentary by Luo and Feng, p. 640

This article is highlighted in the In This Issue feature, p. 621
Data from Mechanism-Based Epigenetic Chemosensitization Therapy of Diffuse Large B-Cell Lymphoma
Authors: Clozel Thomas , Yang ShaoNing , Elstrom Rebecca L. , Tam Wayne , Martin Peter , Kormaksson Matthias , Banerjee Samprit , Vasanthakumar Aparna , Culjkovic Biljana , Scott David W. , Wyman Sarah , Leser Micheal , Shaknovich Rita , Chadburn Amy , Tabbo Fabrizio , Godley Lucy A. , Gascoyne Randy D. , Borden Katherine L. , Inghirami Giorgio , Leonard John P. , Melnick Ari , Cerchietti Leandro
Published: March 2024

Abstract
Although aberrant DNA methylation patterning is a hallmark of cancer, the relevance of targeting DNA methyltransferases (DNMT) remains unclear for most tumors. In diffuse large B-cell lymphoma (DLBCL) we observed that chemoresistance is associated with aberrant DNA methylation programming. Prolonged exposure to low-dose DNMT inhibitors (DNMTI) reprogrammed chemoresistant cells to become doxorubicin sensitive without major toxicity in vivo. Nine genes were recurrently hypermethylated in chemoresistant DLBCL. Of these, SMAD1 was a critical contributor, and reactivation was required for chemosensitization. A phase I clinical study was conducted evaluating azacitidine priming followed by standard chemoimmunotherapy in high-risk patients newly diagnosed with DLBCL. The combination was well tolerated and yielded a high rate of complete remission. Pre- and post-azacitidine treatment biopsies confirmed SMAD1 demethylation and chemosensitization, delineating a personalized strategy for the clinical use of DNMTIs.

Significance: The problem of chemoresistant DLBCL remains the most urgent challenge in the clinical management of patients with this disease. We describe a mechanism-based approach toward the rational translation of DNMTIs for the treatment of high-risk DLBCL. Cancer Discov; 3(9); 1002–19. ©2013 AACR.

See related commentary by Steinhardt and Gartenhaus, p. 968

This article is highlighted in the In This Issue feature, p. 953
Data from MET-Driven Resistance to Dual EGFR and BRAF Blockade May Be Overcome by Switching from EGFR to MET Inhibition in BRAF-Mutated Colorectal Cancer
Authors: Pietrantonio Filippo , Oddo Daniele , Gloghini Annunziata , Valtorta Emanuele , Berenato Rosa , Barault Ludovic , Caporale Marta , Busico Adele , Morano Federica , Gualeni Ambra Vittoria , Alessi Alessandra , Siravegna Giulia , Perrone Federica , Di Bartolomeo Maria , Bardelli Alberto , de Braud Filippo , Di Nicolantonio Federica
Published: March 2024

Abstract
A patient with metastatic BRAF-mutated colorectal cancer initially responded to combined EGFR and BRAF inhibition with panitumumab plus vemurafenib. Pre-existing cells with increased MET gene copy number in the archival tumor tissue likely underwent clonal expansion during treatment, leading to the emergence of MET amplification in the rebiopsy taken at progression. In BRAF-mutated colorectal cancer cells, ectopic expression of MET conferred resistance to panitumumab and vemurafenib, which was overcome by combining BRAF and MET inhibition. Based on tumor genotyping and functional in vitro data, the patient was treated with the dual ALK–MET inhibitor crizotinib plus vemurafenib, thus switching to dual MET and BRAF blockade, with rapid and marked effectiveness of such strategy. Although acquired resistance is a major limitation to the clinical efficacy of anticancer agents, the identification of molecular targets emerging during the first treatment may afford the opportunity to design the next line of targeted therapies, maximizing patient benefit.

Significance: MET amplification is here identified—clinically and preclinically—as a new mechanism of resistance to EGFR and BRAF dual/triple block combinations in BRAF-mutated colorectal cancer. Switching from EGFR to MET inhibition, while maintaining BRAF inhibition, resulted in clinical benefit after the occurrence of MET-driven acquired resistance. Cancer Discov; 6(9); 963–71. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 932
Data from Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development
Authors: Dimitrova Nadya , Gocheva Vasilena , Bhutkar Arjun , Resnick Rebecca , Jong Robyn M. , Miller Kathryn M. , Bendor Jordan , Jacks Tyler
Published: March 2024

Abstract
The two unrelated miRNAs miR-143 and miR-145, coexpressed from the miR-143/145 cluster, have been proposed to act as tumor suppressors in human cancer, and therapeutic benefits of delivering miR-143 and miR-145 to tumors have been reported. In contrast, we found that tumor-specific deletion of miR-143/145 in an autochthonous mouse model of lung adenocarcinoma did not affect tumor development. This was consistent with the lack of endogenous miR-143/145 expression in normal and transformed lung epithelium. Surprisingly, miR-143/145 in the tumor microenvironment dramatically promoted tumor growth by stimulating the proliferation of endothelial cells. Loss of miR-143/145 in vivo led to derepression of the miR-145 target CAMK1D, an inhibitory kinase, which when overexpressed prevents mitotic entry of endothelial cells. As a consequence, tumors in miR-143/145-deficient animals exhibited diminished neoangiogenesis, increased apoptosis, and their expansion was limited by the tumor's ability to co-opt the alveolar vasculature. These findings demonstrate that stromal miR-143/145 promotes tumorigenesis and caution against the use of these miRNAs as agents in cancer therapeutics.

Significance: This study shows that miR-143/145 expressed from the tumor microenvironment stimulates neoangiogenesis and supports tumor expansion in the lung, demonstrating a surprising role for the putative tumor suppressor miRNA cluster in promoting tumorigenesis. We propose inhibition of miR-143/145 as a therapeutic avenue to modulate tumor neoangiogenesis. Cancer Discov; 6(2); 188–201. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 109
Data from IFNγ and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma
Authors: Long Kristen B. , Gladney Whitney L. , Tooker Graham M. , Graham Kathleen , Fraietta Joseph A. , Beatty Gregory L.
Published: March 2024

Abstract
Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this antifibrotic activity, though, remain unclear. Here, we report that IFNγ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C+CCR2+ monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C+ monocyte/macrophage infiltration, IFNγ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMP) in tumors, leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes, leading to enhanced chemotherapy efficacy.

Significance: We report that CD40 agonists improve chemotherapy efficacy in pancreatic carcinoma by redirecting tumor-infiltrating monocytes/macrophages to induce fibrosis degradation that is dependent on MMPs. These findings provide novel insight into the plasticity of monocytes/macrophages in cancer and their capacity to regulate fibrosis and modulate chemotherapy efficacy in pancreatic carcinoma. Cancer Discov; 6(4); 400–13. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 331
Data from STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion
Authors: Gotthardt Dagmar , Putz Eva M. , Grundschober Eva , Prchal-Murphy Michaela , Straka Elisabeth , Kudweis Petra , Heller Gerwin , Bago-Horvath Zsuzsanna , Witalisz-Siepracka Agnieszka , Cumaraswamy Abbarna A. , Gunning Patrick T. , Strobl Birgit , Müller Mathias , Moriggl Richard , Stockmann Christian , Sexl Veronika
Published: March 2024

Abstract
Natural killer (NK) cells are tightly regulated by the JAK–STAT signaling pathway and cannot survive in the absence of STAT5. We now report that STAT5-deficient NK cells can be rescued by overexpression of BCL2. Our experiments define STAT5 as a master regulator of NK-cell proliferation and lytic functions. Although NK cells are generally responsible for killing tumor cells, the rescued STAT5-deficient NK cells promote tumor formation by producing enhanced levels of the angiogenic factor VEGFA. The importance of VEGFA produced by NK cells was verified by experiments with a conditional knockout of VEGFA in NK cells. We show that STAT5 normally represses the transcription of VEGFA in NK cells, in both mice and humans. These findings reveal that STAT5-directed therapies may have negative effects: In addition to impairing NK-cell–mediated tumor surveillance, they may even promote tumor growth by enhancing angiogenesis.

Significance: The importance of the immune system in effective cancer treatment is widely recognized. We show that the new signal interceptors targeting the JAK–STAT5 pathway may have dangerous side effects that must be taken into account in clinical trials: inhibiting JAK–STAT5 has the potential to promote tumor growth by enhancing NK-cell–mediated angiogenesis. Cancer Discov; 6(4); 414–29. ©2016 AACR.

See related commentary by Ni and Cerwenka, p. 347.

This article is highlighted in the In This Issue feature, p. 331
Data from Bruton Tyrosine Kinase–Dependent Immune Cell Cross-talk Drives Pancreas Cancer
Authors: Gunderson Andrew J. , Kaneda Megan M. , Tsujikawa Takahiro , Nguyen Abraham V. , Affara Nesrine I. , Ruffell Brian , Gorjestani Sara , Liudahl Shannon M. , Truitt Morgan , Olson Peter , Kim Grace , Hanahan Douglas , Tempero Margaret A. , Sheppard Brett , Irving Bryan , Chang Betty Y. , Varner Judith A. , Coussens Lisa M.
Published: March 2024

Abstract
Pancreas ductal adenocarcinoma (PDAC) has one of the worst 5-year survival rates of all solid tumors, and thus new treatment strategies are urgently needed. Here, we report that targeting Bruton tyrosine kinase (BTK), a key B-cell and macrophage kinase, restores T cell–dependent antitumor immune responses, thereby inhibiting PDAC growth and improving responsiveness to standard-of-care chemotherapy. We report that PDAC tumor growth depends on cross-talk between B cells and FcRγ+ tumor–associated macrophages, resulting in TH2-type macrophage programming via BTK activation in a PI3Kγ-dependent manner. Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a TH1 phenotype that fostered CD8+ T-cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression. These data indicate that pharmacologic inhibition of BTK in PDAC can reactivate adaptive immune responses, presenting a new therapeutic modality for this devastating tumor type.

Significance: We report that BTK regulates B-cell and macrophage-mediated T-cell suppression in pancreas adenocarcinomas. Inhibition of BTK with the FDA-approved inhibitor ibrutinib restores T cell–dependent antitumor immune responses to inhibit PDAC growth and improves responsiveness to chemotherapy, presenting a new therapeutic modality for pancreas cancer. Cancer Discov; 6(3); 270–85. ©2015 AACR.

See related commentary by Roghanian et al., p. 230.

See related article by Pylayeva-Gupta et al., p. 247.

See related article by Lee et al., p. 256.

This article is highlighted in the In This Issue feature, p. 217
Data from Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia
Authors: Konopleva Marina , Pollyea Daniel A. , Potluri Jalaja , Chyla Brenda , Hogdal Leah , Busman Todd , McKeegan Evelyn , Salem Ahmed Hamed , Zhu Ming , Ricker Justin L. , Blum William , DiNardo Courtney D. , Kadia Tapan , Dunbar Martin , Kirby Rachel , Falotico Nancy , Leverson Joel , Humerickhouse Rod , Mabry Mack , Stone Richard , Kantarjian Hagop , Letai Anthony
Published: March 2024

Abstract
We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.

Significance: Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106–17. ©2016 AACR.

See related commentary by Pullarkat and Newman, p. 1082.

This article is highlighted in the In This Issue feature, p. 1069
Data from DNMT3A Haploinsufficiency Transforms FLT3ITD Myeloproliferative Disease into a Rapid, Spontaneous, and Fully Penetrant Acute Myeloid Leukemia
Authors: Meyer Sara E. , Qin Tingting , Muench David E. , Masuda Kohei , Venkatasubramanian Meenakshi , Orr Emily , Suarez Lauren , Gore Steven D. , Delwel Ruud , Paietta Elisabeth , Tallman Martin S. , Fernandez Hugo , Melnick Ari , Le Beau Michelle M. , Kogan Scott , Salomonis Nathan , Figueroa Maria E. , Grimes H. Leighton
Published: March 2024

Abstract
Cytogenetically normal acute myeloid leukemia (CN-AML) represents nearly 50% of human AML. Co-occurring mutations in the de novo DNA methyltransferase DNMT3A and the FMS related tyrosine kinase 3 (FLT3) are common in CN-AML and confer a poorer prognosis. We demonstrate that mice with Flt3-internal tandem duplication (Flt3ITD) and inducible deletion of Dnmt3a spontaneously develop a rapidly lethal, completely penetrant, and transplantable AML of normal karyotype. AML cells retain a single Dnmt3a floxed allele, revealing the oncogenic potential of Dnmt3a haploinsufficiency. FLT3ITD/DNMT3A-mutant primary human and murine AML exhibit a similar pattern of global DNA methylation associated with changes in the expression of nearby genes. In the murine model, rescuing Dnmt3a expression was accompanied by DNA remethylation and loss of clonogenic potential, suggesting that Dnmt3a-mutant oncogenic effects are reversible. Dissection of the cellular architecture of the AML model using single-cell assays, including single-cell RNA sequencing, identified clonogenic subpopulations that express genes sensitive to the methylation of nearby genomic loci and responsive to DNMT3A levels. Thus, Dnmt3a haploinsufficiency transforms Flt3ITD myeloproliferative disease by modulating methylation-sensitive gene expression within a clonogenic AML subpopulation.

Significance:DNMT3A haploinsufficiency results in reversible epigenetic alterations that transform FLT3ITD-mutant myeloproliferative neoplasm into AML. Cancer Discov; 6(5); 501–15. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 461
Data from A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics
Authors: Sadanandam Anguraj , Wullschleger Stephan , Lyssiotis Costas A. , Grötzinger Carsten , Barbi Stefano , Bersani Samantha , Körner Jan , Wafy Ismael , Mafficini Andrea , Lawlor Rita T. , Simbolo Michele , Asara John M. , Bläker Hendrik , Cantley Lewis C. , Wiedenmann Bertram , Scarpa Aldo , Hanahan Douglas
Published: March 2024

Abstract
Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities.

Significance: This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. Cancer Discov; 5(12); 1296–313. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1225
Data from Superenhancer Analysis Defines Novel Epigenomic Subtypes of Non-APL AML, Including an RARα Dependency Targetable by SY-1425, a Potent and Selective RARα Agonist
Authors: McKeown Michael R. , Corces M. Ryan , Eaton Matthew L. , Fiore Chris , Lee Emily , Lopez Jeremy T. , Chen Mei Wei , Smith Darren , Chan Steven M. , Koenig Julie L. , Austgen Kathryn , Guenther Matthew G. , Orlando David A. , Lovén Jakob , Fritz Christian C. , Majeti Ravindra
Published: March 2024

Abstract
We characterized the enhancer landscape of 66 patients with acute myeloid leukemia (AML), identifying 6 novel subgroups and their associated regulatory loci. These subgroups are defined by their superenhancer (SE) maps, orthogonal to somatic mutations, and are associated with distinct leukemic cell states. Examination of transcriptional drivers for these epigenomic subtypes uncovers a subset of patients with a particularly strong SE at the retinoic acid receptor alpha (RARA) gene locus. The presence of a RARA SE and concomitant high levels of RARA mRNA predisposes cell lines and ex vivo models to exquisite sensitivity to a selective agonist of RARα, SY-1425 (tamibarotene). Furthermore, only AML patient-derived xenograft (PDX) models with high RARA mRNA were found to respond to SY-1425. Mechanistically, we show that the response to SY-1425 in RARA-high AML cells is similar to that of acute promyelocytic leukemia treated with retinoids, characterized by the induction of known retinoic acid response genes, increased differentiation, and loss of proliferation.

Significance: We use the SE landscape of primary human AML to elucidate transcriptional circuitry and identify novel cancer vulnerabilities. A subset of patients were found to have an SE at RARA, which is predictive for response to SY-1425, a potent and selective RARα agonist, in preclinical models, forming the rationale for its clinical investigation in biomarker-selected patients. Cancer Discov; 7(10); 1136–53. ©2017 AACR.

See related commentary by Wang and Aifantis, p. 1065..

This article is highlighted in the In This Issue feature, p. 1047
Data from Reduced Proteolytic Shedding of Receptor Tyrosine Kinases Is a Post-Translational Mechanism of Kinase Inhibitor Resistance
Authors: Miller Miles A. , Oudin Madeleine J. , Sullivan Ryan J. , Wang Stephanie J. , Meyer Aaron S. , Im Hyungsoon , Frederick Dennie T. , Tadros Jenny , Griffith Linda G. , Lee Hakho , Weissleder Ralph , Flaherty Keith T. , Gertler Frank B. , Lauffenburger Douglas A.
Published: March 2024

Abstract
Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTK), including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of patients with melanoma treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured noninvasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

Significance: Genetic, epigenetic, and gene expression alterations often fail to explain adaptive drug resistance in cancer. This work presents a novel post-translational mechanism of such resistance: Kinase inhibitors, particularly targeting MAPK signaling, increase tumor cell surface receptor levels due to widely reduced proteolysis, allowing tumor signaling to circumvent intended drug action. Cancer Discov; 6(4); 382–99. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 331
Data from APC/C Dysfunction Limits Excessive Cancer Chromosomal Instability
Authors: Sansregret Laurent , Patterson James O. , Dewhurst Sally , López-García Carlos , Koch André , McGranahan Nicholas , Chao William Chong Hang , Barry David J. , Rowan Andrew , Instrell Rachael , Horswell Stuart , Way Michael , Howell Michael , Singleton Martin R. , Medema René H. , Nurse Paul , Petronczki Mark , Swanton Charles
Published: March 2024

Abstract
Intercellular heterogeneity, exacerbated by chromosomal instability (CIN), fosters tumor heterogeneity and drug resistance. However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability. Here, we used a functional genomics screen, genome editing, and pharmacologic approaches to identify CIN-survival factors in diploid cells. We find partial anaphase-promoting complex/cyclosome (APC/C) dysfunction lengthens mitosis, suppresses pharmacologically induced chromosome segregation errors, and reduces naturally occurring lagging chromosomes in cancer cell lines or following tetraploidization. APC/C impairment caused adaptation to MPS1 inhibitors, revealing a likely resistance mechanism to therapies targeting the spindle assembly checkpoint. Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN. Subtle variations in mitotic duration, determined by APC/C activity, influence the extent of CIN, allowing cancer cells to dynamically optimize fitness during tumor evolution.

Significance: We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer. Lengthening of mitosis through APC/C modulation may be a common mechanism of resistance to cancer therapeutics that increase chromosome segregation errors. Cancer Discov; 7(2); 218–33. ©2017 AACR.

See related commentary by Burkard and Weaver, p. 134.

This article is highlighted in the In This Issue feature, p. 115
Data from Molecular Heterogeneity and Receptor Coamplification Drive Resistance to Targeted Therapy in MET-Amplified Esophagogastric Cancer
Authors: Kwak Eunice L. , Ahronian Leanne G. , Siravegna Giulia , Mussolin Benedetta , Borger Darrell R. , Godfrey Jason T. , Jessop Nicholas A. , Clark Jeffrey W. , Blaszkowsky Lawrence S. , Ryan David P. , Lennerz Jochen K. , Iafrate A. John , Bardelli Alberto , Hong Theodore S. , Corcoran Ryan B.
Published: March 2024

Abstract
MET inhibition is effective in some patients with MET-amplified esophagogastric cancer (EGC), but understanding acquired and de novo resistance mechanisms will be critical to improving therapy. We identified KRAS mutation as a novel cause of acquired resistance in a patient after a 2-year response to a MET inhibitor. We also observed that 40% to 50% of patients with MET-amplified EGC harbor coamplification of HER2 and/or EGFR concurrently in the same tumor cells, which can drive de novo resistance. One patient with concurrent MET and HER2 amplification was refractory to HER2 blockade, but responded to combined MET/HER2 inhibition. We also found striking heterogeneity in MET amplification between distinct metastatic lesions and primary tumors in individual patients with EGC. In these patients, MET inhibition led to mixed responses and disease progression through outgrowth of non–MET-amplified clones, which could be monitored in circulating tumor DNA. Thus, receptor coamplification and molecular heterogeneity may be key drivers of clinical resistance in MET-amplified EGC.

Significance: Coamplification of driver oncogenes occurs frequently in EGC and can drive therapeutic resistance, supporting a role for comprehensive molecular analysis prior to targeted therapy. EGCs can also exhibit extensive heterogeneity in gene amplification between distinct tumor lesions within the same patient, suggesting that molecular profiling of a single-lesion biopsy may be insufficient to guide targeted therapy selection. Cancer Discov; 5(12); 1271–81. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1225
Data from GM-CSF Mediates Mesenchymal–Epithelial Cross-talk in Pancreatic Cancer
Authors: Waghray Meghna , Yalamanchili Malica , Dziubinski Michele , Zeinali Mina , Erkkinen Marguerite , Yang Huibin , Schradle Kara A. , Urs Sumithra , Pasca Di Magliano Marina , Welling Theodore H. , Palmbos Phillip L. , Abel Ethan V. , Sahai Vaibhav , Nagrath Sunitha , Wang Lidong , Simeone Diane M.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer–associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis.

Significance: The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal–epithelial cross-talk and is amenable to therapeutic intervention. Cancer Discov; 6(8); 886–99. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 803
Data from BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
Authors: Tasdemir Nilgun , Banito Ana , Roe Jae-Seok , Alonso-Curbelo Direna , Camiolo Matthew , Tschaharganeh Darjus F. , Huang Chun-Hao , Aksoy Ozlem , Bolden Jessica E. , Chen Chi-Chao , Fennell Myles , Thapar Vishal , Chicas Agustin , Vakoc Christopher R. , Lowe Scott W.
Published: March 2024

Abstract
Oncogene-induced senescence is a potent barrier to tumorigenesis that limits cellular expansion following certain oncogenic events. Senescent cells display a repressive chromatin configuration thought to stably silence proliferation-promoting genes while simultaneously activating an unusual form of immune surveillance involving a secretory program referred to as the senescence-associated secretory phenotype (SASP). Here, we demonstrate that senescence also involves a global remodeling of the enhancer landscape with recruitment of the chromatin reader BRD4 to newly activated super-enhancers adjacent to key SASP genes. Transcriptional profiling and functional studies indicate that BRD4 is required for the SASP and downstream paracrine signaling. Consequently, BRD4 inhibition disrupts immune cell–mediated targeting and elimination of premalignant senescent cells in vitro and in vivo. Our results identify a critical role for BRD4-bound super-enhancers in senescence immune surveillance and in the proper execution of a tumor-suppressive program.

Significance: This study reveals how cells undergoing oncogene-induced senescence acquire a distinctive enhancer landscape that includes formation of super-enhancers adjacent to immune-modulatory genes required for paracrine immune activation. This process links BRD4 and super-enhancers to a tumor-suppressive immune surveillance program that can be disrupted by small molecule inhibitors of the bromo and extra terminal domain family of proteins. Cancer Discov; 6(6); 612–29. ©2016 AACR.

See related commentary by Vizioli and Adams, p. 576.

This article is highlighted in the In This Issue feature, p. 561
Data from Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation
Authors: Elf Shannon , Abdelfattah Nouran S. , Chen Edwin , Perales-Patón Javier , Rosen Emily A. , Ko Amy , Peisker Fabian , Florescu Natalie , Giannini Silvia , Wolach Ofir , Morgan Elizabeth A. , Tothova Zuzana , Losman Julie-Aurore , Schneider Rebekka K. , Al-Shahrour Fatima , Mullally Ann
Published: March 2024

Abstract
Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK–STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN.

Significance: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL. Cancer Discov; 6(4); 368–81. ©2016 AACR.

See related commentary by Stanley and Steidl, p. 344.

This article is highlighted in the In This Issue feature, p. 331
Data from A Large Multiethnic Genome-Wide Association Study of Prostate Cancer Identifies Novel Risk Variants and Substantial Ethnic Differences
Authors: Hoffmann Thomas J. , Van Den Eeden Stephen K. , Sakoda Lori C. , Jorgenson Eric , Habel Laurel A. , Graff Rebecca E. , Passarelli Michael N. , Cario Clinton L. , Emami Nima C. , Chao Chun R. , Ghai Nirupa R. , Shan Jun , Ranatunga Dilrini K. , Quesenberry Charles P. , Aaronson David , Presti Joseph , Wang Zhaoming , Berndt Sonja I. , Chanock Stephen J. , McDonnell Shannon K. , French Amy J. , Schaid Daniel J. , Thibodeau Stephen N. , Li Qiyuan , Freedman Matthew L. , Penney Kathryn L. , Mucci Lorelei A. , Haiman Christopher A. , Henderson Brian E. , Seminara Daniela , Kvale Mark N. , Kwok Pui-Yan , Schaefer Catherine , Risch Neil , Witte John S.
Published: March 2024

Abstract
A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10−19 (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10−23) and SLC22A3 (P = 3.2 × 10−52). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10−13; OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 × 10−8). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004).

Significance: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. Cancer Discov; 5(8); 878–91. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 783