Immune checkpoint blockade (ICB) therapy has achieved breakthroughs in the treatment of advanced non-small cell lung cancer (NSCLC). Nevertheless, the low response due to immuno-cold tumor microenvironment (TME) largely limits the application of ICB therapy. Based on the glycolytic/cholesterol synthesis axis, a stratification framework for EGFR wild-type NSCLC was developed to summarize the metabolic features of immuno-cold and immuno-hot tumors. The cholesterol subgroup displays the worst prognosis in immuno-cold NSCLC with significant enrichment of the cholesterol gene signature, indicating targeting cholesterol synthesis is essential for the therapy for immuno-cold NSCLC. Statin, the inhibitor for cholesterol synthesis, can suppress the aggressiveness of NSCLC in vitro and in vivo and also drastically reverse immuno-cold to an inflamed phenotype in vivo which exhibited a higher response to ICB therapy. Moreover, both our in-house data and meta-analysis further support that statin can significantly enhance ICB efficacy. In terms of preliminary mechanisms, statin could transcriptionally inhibit PD-L1 expression and induce ferroptosis in NSCLC cells. Overall, we reveal the significance of cholesterol synthesis in NSCLC and demonstrate the improved therapeutic efficacy of ICB in combination with statin. These findings could provide a innovative clinical insight to treat NSCLC patients with immuno-cold tumors.
Wenjun Mao, Yun Cai, Danrong Chen, Guanyu Jiang, Yongrui Xu, Ruo Chen, Fengxu Wang, Xuehai Wang, Mingfeng Zheng, Xinyuan Zhao, Jie Mei
Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multi-omic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening and transcriptomic data across >700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of <10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in three different neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma and we propose this combination for clinical testing.
Thale Kristin Olsen, Cecilia Dyberg, Bethel Tesfai Embaie, Adele M. Alchahin, Jelena Milosevic, Jane Ding, Jörg Otte, Conny Tümmler, Ida Hed Myrberg, Ellen M. Westerhout, Jan Koster, Rogier Versteeg, Han-Fei Ding, Per Kogner, John Inge Johnsen, David B. Sykes, Ninib Baryawno
The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape of this disease across disease states. We uniformly characterized structural alterations across 531 localized and 143 metastatic prostate cancers profiled by whole genome sequencing, 125 metastatic samples of which were also profiled via whole transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes enriched in mCRPC and TMPRSS2-ERG rearrangements enriched in localized prostate cancer. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.
Meng Zhou, Minjeong Ko, Anna C.H. Hoge, Kelsey Luu, Yuzhen Liu, Magdalena L. Russell, William W. Hannon, Zhenwei Zhang, Jian Carrot-Zhang, Rameen Beroukhim, Eliezer M. Van Allen, Atish D. Choudhury, Peter S. Nelson, Matthew Freedman, Mary-Ellen Taplin, Matthew Meyerson, Srinivas R. Viswanathan, Gavin Ha
Acquired mutations in the ligand-binding domain (LBD) of the gene encoding Estrogen Receptor alpha (ESR1) are a common mechanism of endocrine therapy resistance in metastatic ER-positive breast cancer patients. ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1200 Federal Drug Administration (FDA)-approved drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib+fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with wild-type cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.
Sm N. Udden, Qian Wang, Sunil Kumar, Venkat S. Malladi, Shwu-Yuan Wu, Shuguang Wei, Bruce A. Posner, Sophie Geboers, Noelle S. Williams, Yu-Lun Liu, Jayesh K. Sharma, Ram S. Mani, Srinivas Malladi, Karla Parra, Mia Hofstad, Ganesh V. Raj, Jose M. Larios, Reshma Jagsi, Max S. Wicha, Ben Ho Park, Gaorav P. Gupta, Arul M. Chinnaiyan, Cheng-Ming Chiang, Prasanna G. Alluri
Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown with a dearth of accurate pre-clinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment naïve (RTU) PDX. These unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole exome sequencing confirmed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that is associated with clinical GBM recurrence in two RTS models. A novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic and kinomic alterations, which identified long non-coding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair (DDR) pathways in our RTS models which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation-resistance. RTS model-specific kinases were identified and targeted with clinically relevant small molecule inhibitors (SMIs). This unique cohort of in vivo radiation therapy-selected patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in GBM patients.
Christian T. Stackhouse, Joshua C. Anderson, Zongliang Yue, Thanh Nguyen, Nicholas J. Eustace, Catherine P. Langford, Jelai Wang, James R. Rowland IV, Chuan Xing, Fady M. Mikhail, Xiangqin Cui, Hasan Alrefai, Ryan E. Bash, Kevin J. Lee, Eddy S. Yang, Anita B. Hjelmeland, C. Ryan Miller, Jake Y. Chen, G. Yancey Gillespie, Christopher D. Willey
Metastatic urothelial carcinoma is generally incurable with current systemic therapies. Chromatin modifiers are frequently mutated in bladder cancer, with ARID1A-inactivating mutations present in about 20% of tumors. EZH2, a histone methyltransferase, acts as an oncogene that functionally opposes ARID1A. In addition, PI3K signaling is activated in more than 20% of bladder cancers. Using a combination of in vitro and in vivo data, including patient derived xenografts, we show that ARID1A-mutant tumors are more sensitive to EZH2 inhibition than ARID1A-wild type tumors. Mechanistic studies reveal that: 1) ARID1A deficiency results in a dependency on PI3K/AKT/mTOR signaling via novel upregulation of a non-canonical PI3K regulatory subunit, PIK3R3, and downregulation of MAPK signaling, and: 2) EZH2 inhibitor sensitivity is due to upregulation of PIK3IP1, a protein inhibitor of PI3K signaling. We show for the first time that PIK3IP1 inhibits PI3K signaling by inducing proteasomal degradation of PIK3R3. Further, ARID1A deficient bladder cancer is sensitive to combination therapies with EZH2 and PI3K inhibitors, in a synergistic manner. Thus, our studies suggest that bladder cancers with ARID1A mutations can be treated with inhibitors of EZH2 and/or PI3K, and reveal mechanistic insights into the role of non-canonical PI3K constituents in bladder cancer biology.
Hasibur Rehman, Darshan S. Chandrashekar, Chakravarthi Balabhadrapatruni, Saroj Nepal, Sai Akshaya Hodigere Balasubramanya, Abigail K. Shelton, Kasey R. Skinner, Ai-Hong Ma, Ting Rao, Marie-Lisa Eich, Alyncia D. Robinson, Gurudatta Naik, Upender Manne, George J. Netto, C. Ryan Miller, Chong-xian Pan, Guru Sonpavde, Sooryanarayana Varambally, James E. Ferguson 3rd
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin with 2 etiologies. Merkel cell polyomavirus (MCPyV) integration is present in about 80% of all MCC. Virus-positive MCC (MCCP) tumors have few somatic mutations and usually express WT p53 (TP53). By contrast, virus-negative MCC (MCCN) tumors present with a high tumor mutational burden and predominantly UV mutational signature. MCCN tumors typically contain mutated TP53. MCCP tumors express 2 viral proteins: MCPyV small T antigen and a truncated form of large T antigen. MCPyV ST specifically activates expression of MDM2, an E3 ubiquitin ligase of p53, to inhibit p53-mediated tumor suppression. In this study, we assessed the efficacy of milademetan, a potent, selective, and orally available MDM2 inhibitor in several MCC models. Milademetan reduced cell viability of WT p53 MCC cell lines and triggered a rapid and sustained p53 response. Milademetan showed a dose-dependent inhibition of tumor growth in MKL-1 xenograft and patient-derived xenograft models. Here, along with preclinical data for the efficacy of milademetan in WT p53 MCC tumors, we report several in vitro and in vivo models useful for future MCC studies.
Varsha Ananthapadmanabhan, Thomas C. Frost, Kara M. Soroko, Aine Knott, Brianna J. Magliozzi, Prafulla C. Gokhale, Vijaya G. Tirunagaru, Robert C. Doebele, James A. DeCaprio
NLRP3 inflammasome and interferon stimulated gene (ISG) induction are key biological drivers of ineffective hematopoiesis and inflammation in Myelodysplastic Syndromes (MDS). Gene mutations involving messenger RNA splicing and epigenetic regulatory pathways induce inflammasome activation and myeloid lineage skewing in MDS through yet undefined mechanisms. Using immortalized murine hematopoietic stem and progenitor cells harboring these somatic gene mutations and primary MDS bone marrow specimens, we show accumulation of unresolved R-loops and micronuclei with concurrent activation of the cytosolic sensor, cGAS. cGAS-STING signaling caused interferon stimulated gene (ISG) induction, NLRP3 inflammasome activation, and maturation of the effector protease, caspase-1. Deregulation of RNA polymerase III drives cytosolic R-loop generation, which upon inhibition, extinguishes ISG and inflammasome response. Mechanistically, caspase-1 degrades the master erythroid transcription factor, GATA1, provoking anemia and myeloid lineage bias that is reversed by cGAS inhibition in vitro and in Tet2-/- hematopoietic stem and progenitor cell transplanted mice. Together, these data identity a novel mechanism by which functionally distinct mutations converge upon the cGAS-STING-NLRP3 axis in MDS directing ISG induction, pyroptosis and myeloid lineage skewing.
Amy F. McLemore, Hsin-An Hou, Benjamin S. Meyer, Nghi B. Lam, Grace A. Ward, Amy L. Aldrich, Matthew A. Rodrigues, Alexis Vedder, Ling Zhang, Eric Padron, Nicole D. Vincelette, David A. Sallman, Omar Abdel-Wahab, Alan F. List, Kathy L. McGraw
Integrins, the principal extracellular matrix (ECM) receptors of the cell, promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin β1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin β1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin β1-mediated adhesion to ECM but are dependent on integrin β1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). Together, these studies support a critical role for integrin β1 in lung tumorigenesis that is mediated through constitutive, ECM-binding independent signaling involving the cytoplasmic tail.
Scott M. Haake, Erin J. Plosa, Jonathan A. Kropski, Lindsay A. Venton, Anupama Reddy, Fabian Bock, Betty T. Chang, Allen J. Luna, Kateryna Nabukhotna, Zhi-Qi Xu, Rebecca A. Prather, Sharon Lee, Harikrishna Tanjore, Vasiliy V. Polosukhin, Olga M. Viquez, Angela Jones, Wentian Luo, Matthew H. Wilson, W. Kimryn Rathmell, Pierre P. Massion, Ambra Pozzi, Timothy S. Blackwell, Roy Zent
Novel therapeutic strategies, including immunotherapeutics, targeting glioblastoma (GBM) often fail in the clinic, at least partly because available preclinical models in which hypotheses are being tested, do not recapitulate the human disease. To address this challenge, we took advantage of our previously developed spontaneous Qk/trp53/Pten (QPP) triple-knockout model of human GBM, and compared its immune microenvironment components with those of patient-derived tumors in effort to determine whether this model might provide an opportunity for gaining insights into tumor physiopathology as well as for preclinical evaluation of therapeutic agents. Immune profiling analyses and single-cell sequencing of implanted and spontaneous tumors from QPP mice as well as from GBM patients revealed intratumoral immune components that were predominantly myeloid cells (e.g. monocytes, macrophages, and microglia) with minor populations of T, B, and NK cells. When comparing spontaneous and implanted mouse samples, we found that there were more neutrophils, T and NK cells in the implanted model. Neutrophils, T and NK cells were increased in abundance in samples derived from human high-grade glioma (HGG) compared to those derived from low grade glioma (LGG). Overall, our data demonstrate that our implanted and spontaneous QPP models recapitulate the immunosuppressive myeloid dominant nature of the tumor microenvironment of human gliomas. Our model provides a suitable tool for investigating the complex immune compartment of gliomas and it may contribute to a better understanding of the resistance of human glioblastoma to currently available immunotherapeutics.
Daniel B. Zamler, Takashi Shingu, Laura M. Kahn, Kristin Huntoon, Cynthia Kassab, Martina Ott, Katarzyna Tomczak, Jintan Liu, Yating Li, Ivy Lai, Rocio Zorilla-Veloz, Cassian Yee, Kunal Rai, Betty Y.S. Kim, Stephanie S. Watowich, Amy B. Heimberger, Giulio F. Draetta, Jian Hu
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