A Pharmacogenomic Landscape in Human Liver Cancers Publication date: Available online 1 August 2019 Source: Cancer Cell Author(s): Zhixin Qiu, Hong Li, Zhengtao Zhang, Zhenfeng Zhu, Sheng He, Xujun Wang, Pengcheng Wang, Jianjie Qin, Liping Zhuang, Wei Wang, Fubo Xie, Ying Gu, Keke Zou, Chao Li, Chun Li, Chenhua Wang, Jin Cen, Xiaotao Chen, Yajing Shu, Zhao Zhang Summary Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers. Graphical Abstract

Protein Kinase Cι and Wnt/β-Catenin Signaling: Alternative Pathways to Kras/Trp53-Driven Lung Adenocarcinoma Publication date: Available online 1 August 2019 Source: Cancer Cell Author(s): Ning Yin, Yi Liu, Andras Khoor, Xue Wang, E. Aubrey Thompson, Michael Leitges, Verline Justilien, Capella Weems, Nicole R. Murray, Alan P. Fields Summary We report that mouse LSL-KrasG12D;Trp53fl/fl (KP)-mediated lung adenocarcinoma (LADC) tumorigenesis can proceed through both PKCι-dependent and PKCι-independent pathways. The predominant pathway involves PKCι-dependent transformation of bronchoalveolar stem cells (BASCs). However, KP mice harboring conditional knock out Prkci alleles (KPI mice) develop LADC tumors through PKCι-independent transformation of Axin2+ alveolar type 2 (AT2) stem cells. Transformed growth of KPI, but not KP, tumors is blocked by Wnt pathway inhibition in vitro and in vivo. Furthermore, a KPI-derived genomic signature predicts sensitivity of human LADC cells to Wnt inhibition, and identifies a distinct subset of primary LADC tumors exhibiting a KPI-like genotype. Thus, LADC can develop through both PKCι-dependent and PKCι-independent pathways, resulting in tumors exhibiting distinct oncogenic signaling and pharmacologic vulnerabilities. Graphical Abstract

The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression Publication date: Available online 18 July 2019 Source: Cancer Cell Author(s): Wenjing Su, Hyun Ho Han, Yan Wang, Boyu Zhang, Bing Zhou, Yuanming Cheng, Alekya Rumandla, Sreeharsha Gurrapu, Goutam Chakraborty, Jie Su, Guangli Yang, Xin Liang, Guocan Wang, Neal Rosen, Howard I. Scher, Ouathek Ouerfelli, Filippo G. Giancotti Summary The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor-associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis. A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC. Graphical Abstract

Removal of N-Linked Glycosylation Enhances PD-L1 Detection and Predicts Anti-PD-1/PD-L1 Therapeutic Efficacy Publication date: Available online 18 July 2019 Source: Cancer Cell Author(s): Heng-Huan Lee, Ying-Nai Wang, Weiya Xia, Chia-Hung Chen, Kun-Ming Rau, Leiguang Ye, Yongkun Wei, Chao-Kai Chou, Shao-Chun Wang, Meisi Yan, Chih-Yen Tu, Te-Chun Hsia, Shu-Fen Chiang, K.S. Clifford Chao, Ignacio I. Wistuba, Jennifer L. Hsu, Gabriel N. Hortobagyi, Mien-Chie Hung Summary Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy. Graphical Abstract

Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome Publication date: Available online 11 July 2019 Source: Cancer Cell Author(s): Maurice Labuhn, Kelly Perkins, Sören Matzk, Leila Varghese, Catherine Garnett, Elli Papaemmanuil, Marlen Metzner, Alison Kennedy, Vyacheslav Amstislavskiy, Thomas Risch, Raj Bhayadia, David Samulowski, David Cruz Hernandez, Bilyana Stoilova, Valentina Iotchkova, Udo Oppermann, Carina Scheer, Kenichi Yoshida, Adrian Schwarzer, Jeffrey Taub Summary Myeloid leukemia in Down syndrome (ML-DS) clonally evolves from transient abnormal myelopoiesis (TAM), a preleukemic condition in DS newborns. To define mechanisms of leukemic transformation, we combined exome and targeted resequencing of 111 TAM and 141 ML-DS samples with functional analyses. TAM requires trisomy 21 and truncating mutations in GATA1; additional TAM variants are usually not pathogenic. By contrast, in ML-DS, clonal and subclonal variants are functionally required. We identified a recurrent and oncogenic hotspot gain-of-function mutation in myeloid cytokine receptor CSF2RB. By a multiplex CRISPR/Cas9 screen in an in vivo murine TAM model, we tested loss-of-function of 22 recurrently mutated ML-DS genes. Loss of 18 different genes produced leukemias that phenotypically, genetically, and transcriptionally mirrored ML-DS. Graphical Abstract

Pan-cancer Convergence to a Small-Cell Neuroendocrine Phenotype that Shares Susceptibilities with Hematological Malignancies Publication date: 8 July 2019 Source: Cancer Cell, Volume 36, Issue 1 Author(s): Nikolas G. Balanis, Katherine M. Sheu, Favour N. Esedebe, Saahil J. Patel, Bryan A. Smith, Jung Wook Park, Salwan Alhani, Brigitte N. Gomperts, Jiaoti Huang, Owen N. Witte, Thomas G. Graeber Summary Small-cell neuroendocrine cancers (SCNCs) are an aggressive cancer subtype. Transdifferentiation toward an SCN phenotype has been reported as a resistance route in response to targeted therapies. Here, we identified a convergence to an SCN state that is widespread across epithelial cancers and is associated with poor prognosis. More broadly, non-SCN metastases have higher expression of SCN-associated transcription factors than non-SCN primary tumors. Drug sensitivity and gene dependency screens demonstrate that these convergent SCNCs have shared vulnerabilities. These common vulnerabilities are found across unannotated SCN-like epithelial cases, small-round-blue cell tumors, and unexpectedly in hematological malignancies. The SCN convergent phenotype and common sensitivity profiles with hematological cancers can guide treatment options beyond tissue-specific targeted therapies. Graphical Abstract

Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading? Publication date: 8 July 2019 Source: Cancer Cell, Volume 36, Issue 1 Author(s): Stefan Mereiter, Meritxell Balmaña, Diana Campos, Joana Gomes, Celso A. Reis This review provides insights on the impact of glycosylation in cancer biology and its influence in the current approaches of targeted cancer therapies in the clinical setting. The roles of glycosylation in cancer signaling, tumor progression, and metastasis are reviewed as well as glycans and glycan-binding proteins in tumor immunomodulation. Moreover, the latest reports on glycans influencing targeted therapeutic approaches in cancer are summarized. Finally, we discuss the future challenges of the field, outlining potential applications of glycan-based biomarkers for patient stratification and strategies for improving personalized cancer treatment.

M-TAP Dance: Targeting PRMT1 and PRMT5 Family Members to Push Cancer Cells Over the Edge Publication date: 8 July 2019 Source: Cancer Cell, Volume 36, Issue 1 Author(s): Nivine Srour, Sofiane Y. Mersaoui, Stéphane Richard In this issue of Cancer Cell, Fedoriw and colleagues characterize a potent reversible inhibitor of type I PRMTs, GSK3368715, with anti-proliferative effects on numerous cancer types. Using a combination of GSK3368715 with PRMT5 inhibitors, the authors show that a threshold of overall arginine methylation reduction needs to be achieved for synergistic anti-tumor activity.

The Stromal and Immune Landscape of Colorectal Cancer Progression during Anti-EGFR Therapy Publication date: 8 July 2019 Source: Cancer Cell, Volume 36, Issue 1 Author(s): Irene Catalano, Livio Trusolino In this issue of Cancer Cell, Woolston et al. show that colorectal cancers that become refractory to initially effective anti-EGFR therapy contain an abundance of stromal and immune cells, irrespective of the contextual presence of resistance-conferring mutations. This reconfiguration puts forward therapeutic opportunities for patients who relapse on EGFR-targeting treatment.

Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss Publication date: 8 July 2019 Source: Cancer Cell, Volume 36, Issue 1 Author(s): Andrew Fedoriw, Satyajit R. Rajapurkar, Shane O'Brien, Sarah V. Gerhart, Lorna H. Mitchell, Nicholas D. Adams, Nathalie Rioux, Trupti Lingaraj, Scott A. Ribich, Melissa B. Pappalardi, Niyant Shah, Jenny Laraio, Yan Liu, Michael Butticello, Chris L. Carpenter, Caretha Creasy, Susan Korenchuk, Michael T. McCabe, Charles F. McHugh, Raman Nagarajan Summary Type I protein arginine methyltransferases (PRMTs) catalyze asymmetric dimethylation of arginines on proteins. Type I PRMTs and their substrates have been implicated in human cancers, suggesting inhibition of type I PRMTs may offer a therapeutic approach for oncology. The current report describes GSK3368715 (EPZ019997), a potent, reversible type I PRMT inhibitor with anti-tumor effects in human cancer models. Inhibition of PRMT5, the predominant type II PRMT, produces synergistic cancer cell growth inhibition when combined with GSK3368715. Interestingly, deletion of the methylthioadenosine phosphorylase gene (MTAP) results in accumulation of the metabolite 2-methylthioadenosine, an endogenous inhibitor of PRMT5, and correlates with sensitivity to GSK3368715 in cell lines. These data provide rationale to explore MTAP status as a biomarker strategy for patient selection. Graphical Abstract