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KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition

Pan, Yuanwang; Han, Han; Hu, Hai; Wang, Hua; Song, Yueqiang; Hao, Yuan; Tong, Xinyuan; Patel, Ayushi S; Misirlioglu, Selim; Tang, Sittinon; Huang, Hsin-Yi; Geng, Ke; Chen, Ting; Karatza, Angeliki; Sherman, Fiona; Labbe, Kristen E; Yang, Fan; Chafitz, Alison; Peng, Chengwei; Guo, Chenchen; Moreira, Andre L; Velcheti, Vamsidhar; Lau, Sally C M; Sui, Pengfei; Chen, Haiquan; Diehl, J Alan; Rustgi, Anil K; Bass, Adam J; Poirier, John T; Zhang, Xiaoyang; Ji, Hongbin; Zhang, Hua; Wong, Kwok-Kin
Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.
PMID: 36525973
ISSN: 1878-3686
CID: 5382562

Tumor suppressor mediated ubiquitylation of hnRNPK is a barrier to oncogenic translation

Mucha, Bartosz; Qie, Shuo; Bajpai, Sagar; Tarallo, Vincenzo; Diehl, J Nathaniel; Tedeschi, Frank; Zhou, Gao; Gao, Zhaofeng; Flashner, Samuel; Klein-Szanto, Andres J; Hibshoosh, Hanina; Masataka, Shimonosono; Chajewski, Olga S; Majsterek, Ireneusz; Pytel, Dariusz; Hatzoglou, Maria; Der, Channing J; Nakagawa, Hiroshi; Bass, Adam J; Wong, Kwok-Kin; Fuchs, Serge Y; Rustgi, Anil K; Jankowsky, Eckhard; Diehl, J Alan
Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) is a multifunctional RNA binding protein (RBP) localized in the nucleus and the cytoplasm. Abnormal cytoplasmic enrichment observed in solid tumors often correlates with poor clinical outcome. The mechanism of cytoplasmic redistribution and ensuing functional role of cytoplasmic hnRNPK remain unclear. Here we demonstrate that the SCFFbxo4 E3 ubiquitin ligase restricts the pro-oncogenic activity of hnRNPK via K63 linked polyubiquitylation, thus limiting its ability to bind target mRNA. We identify SCFFbxo4-hnRNPK responsive mRNAs whose products regulate cellular processes including proliferation, migration, and invasion. Loss of SCFFbxo4 leads to enhanced cell invasion, migration, and tumor metastasis. C-Myc was identified as one target of SCFFbxo4-hnRNPK. Fbxo4 loss triggers hnRNPK-dependent increase in c-Myc translation, thereby contributing to tumorigenesis. Increased c-Myc positions SCFFbxo4-hnRNPK dysregulated cancers for potential therapeutic interventions that target c-Myc-dependence. This work demonstrates an essential role for limiting cytoplasmic hnRNPK function in order to maintain translational and cellular homeostasis.
PMID: 36329064
ISSN: 2041-1723
CID: 5371412

The current state of the art and future trends in RAS-targeted cancer therapies

Punekar, Salman R; Velcheti, Vamsidhar; Neel, Benjamin G; Wong, Kwok-Kin
Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRASG12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.
PMID: 36028717
ISSN: 1759-4782
CID: 5331872


Fushimi, Atsushi; Morimoto, Yoshihiro; Ishikawa, Satoshi; Yamashita, Nami; Bhattacharya, Atrayee; Daimon, Tatsuaki; Rajabi, Hasan; Jin, Caining; Hagiwara, Masayuki; Yasumizu, Yota; Luan, Zhou; Suo, Wenhao; Wong, Kwok-Kin; Withers, Henry; Liu, Song; Long, Mark D; Kufe, Donald
Small cell lung cancer (SCLC) is a recalcitrant malignancy defined by subtypes based on differential expression of the ASCL1, NEUROD1 and POU2F3 transcription factors. The MUC1-C protein is activated in pulmonary epithelial cells by exposure to environmental carcinogens and promotes oncogenesis; however, there is no known association between MUC1-C and SCLC. We report that MUC1-C is expressed in classic neuroendocrine (NE) SCLC-A, variant NE SCLC-N and non-NE SCLC-P cells and activates the MYC pathway in these subtypes. In SCLC cells characterized by NE differentiation and DNA replication stress, we show that MUC1-C activates the MYC pathway in association with induction of E2F target genes and dysregulation of mitotic progression. Our studies further demonstrate that the MUC1-C->MYC pathway is necessary for induction of (i) NOTCH2, a marker of pulmonary NE stem cells that are the proposed cell of SCLC origin, and (ii) ASCL1 and NEUROD1. We also show that the MUC1-C->MYC->NOTCH2 network is necessary for self-renewal capacity and tumorigenicity of NE and non-NE SCLC cells. Analyses of datasets from SCLC tumors confirmed that MUC1 expression in single SCLC cells significantly associates with activation of the MYC pathway. These findings demonstrate that SCLC cells are addicted to MUC1-C and identify a potential new target for SCLC treatment. Implications: The present work uncovers addiction of SCLC cells to MUC1-C, which is a druggable target that could provide new opportunities for advancing SCLC treatment.
PMID: 35612556
ISSN: 1557-3125
CID: 5248002

DNA methylation profiling identifies subgroups of lung adenocarcinoma with distinct immune cell composition, DNA methylation age, and clinical outcome

Guidry, Kayla; Vasudevaraja, Varshini; Labbe, Kristen; Mohamed, Hussein; Serrano, Jonathan; Guidry, Brett W; DeLorenzo, Michael; Zhang, Hua; Deng, Jiehui; Sahu, Soumyadip; Almonte, Christina; Moreira, Andre L; Tsirigos, Aristotelis; Papagiannakopoulos, Thales; Pass, Harvey; Snuderl, Matija; Wong, Kwok-Kin
PURPOSE/OBJECTIVE:Lung adenocarcinoma (LUAD) is a clinically heterogenous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation-based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs. EXPERIMENTAL DESIGN/METHODS:We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups. RESULTS:Deconvolution of DNA methylation data identified immunologically hot and cold subsets of lung adenocarcinomas. Additionally, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified 6 molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics. CONCLUSIONS:Our results demonstrate that DNA methylation signatures can stratify lung adenocarcinoma into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.
PMID: 35802677
ISSN: 1557-3265
CID: 5280672

Nemvaleukin alfa, a novel engineered IL-2 fusion protein, drives antitumor immunity and inhibits tumor growth in small cell lung cancer

Pan, Yuanwang; Hao, Yuan; Han, Han; Chen, Ting; Ding, Hailin; Labbe, Kristen E; Shum, Elaine; Guidry, Kayla; Hu, Hai; Sherman, Fiona; Geng, Ke; Stephens, Janaye; Chafitz, Alison; Tang, Sittinon; Huang, Hsin-Yi; Peng, Chengwei; Almonte, Christina; Lopes, Jared E; Losey, Heather C; Winquist, Raymond J; Velcheti, Vamsidhar; Zhang, Hua; Wong, Kwok-Kin
BACKGROUND:T cells. Here, using a novel SCLC murine model, we investigated the effects of a mouse version of nemvaleukin (mNemvaleukin) on tumor growth and antitumor immunity. METHODS:SCLC model that mimics human disease was generated. After confirming tumor burden by MRI, mice were randomized into four treatment groups: vehicle, mNemvaleukin alone, chemotherapy (cisplatin+etoposide) alone, or the combination of mNemvaleukin and chemotherapy. Tumor growth was measured by MRI and survival was recorded. Tumor-infiltrating lymphocytes and peripheral blood immune cells were analyzed by flow cytometry. Cytokine and chemokine secretion were quantified and transcriptomic analysis was performed to characterize the immune gene signatures. RESULTS:T cells. mNemvaleukin alone, and in combination with chemotherapy, promoted proinflammatory cytokine and chemokine production, which was further confirmed by transcriptomic analysis. CONCLUSIONS:mNemvaleukin, a novel cytokine-based immunotherapy, significantly inhibited murine SCLC tumor growth and prolonged survival, which was further enhanced by the addition of chemotherapy. mNemvaleukin alone, and in combination with chemotherapy, drove a strong antitumor immune program elicited by cytotoxic immune cells. Our findings support the evaluation of nemvaleukin alone or in combination with chemotherapy in clinical trials for the treatment of SCLC.
PMID: 36472839
ISSN: 2051-1426
CID: 5378672

Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis

Jin, Yujuan; Zhao, Qiqi; Zhu, Weikang; Feng, Yan; Xiao, Tian; Zhang, Peng; Jiang, Liyan; Hou, Yingyong; Guo, Chenchen; Huang, Hsinyi; Chen, Yabin; Tong, Xinyuan; Cao, Jiayu; Li, Fei; Zhu, Xueliang; Qin, Jun; Gao, Dong; Liu, Xin-Yuan; Zhang, Hua; Chen, Luonan; Thomas, Roman K; Wong, Kwok-Kin; Zhang, Lei; Wang, Yong; Hu, Liang; Ji, Hongbin
Small-cell lung cancer (SCLC) is a recalcitrant cancer characterized by high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using a Rb1 L/L /Trp53 L/L mouse model, we identify the NCAMhiCD44lo/- subpopulation as the SCLC metastasizing cell (SMC), which is progressively transitioned from the non-metastasizing NCAMloCD44hi cell (non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal the important role of the SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by the SWI/SNF complex during SCLC malignant progression, and its knockdown promotes SMC transition and metastasis. Importantly, ectopic TAZ expression reversely drives SMC-to-non-SMC transition and alleviates metastasis. Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis, and immunostaining data show a positive correlation between TAZ and patient prognosis. These data uncover high SCLC plasticity and identify TAZ as the key molecular switch in orchestrating SCLC phenotypic transition and metastasis.
PMID: 35967587
ISSN: 2053-714x
CID: 5299742

Therapeutic targeting of the mevalonate-geranylgeranyl diphosphate pathway with statins overcomes chemotherapy resistance in small cell lung cancer

Guo, Chenchen; Wan, Ruijie; He, Yayi; Lin, Shu-Hai; Cao, Jiayu; Qiu, Ying; Zhang, Tengfei; Zhao, Qiqi; Niu, Yujia; Jin, Yujuan; Huang, Hsin-Yi; Wang, Xue; Tan, Li; Thomas, Roman K; Zhang, Hua; Chen, Luonan; Wong, Kwok-Kin; Hu, Liang; Ji, Hongbin
Small cell lung cancer (SCLC) lacks effective treatments to overcome chemoresistance. Here we established multiple human chemoresistant xenograft models through long-term intermittent chemotherapy, mimicking clinically relevant therapeutic settings. We show that chemoresistant SCLC undergoes metabolic reprogramming relying on the mevalonate (MVA)-geranylgeranyl diphosphate (GGPP) pathway, which can be targeted using clinically approved statins. Mechanistically, statins induce oxidative stress accumulation and apoptosis through the GGPP synthase 1 (GGPS1)-RAB7A-autophagy axis. Statin treatment overcomes both intrinsic and acquired SCLC chemoresistance in vivo across different SCLC PDX models bearing high GGPS1 levels. Moreover, we show that GGPS1 expression is negatively associated with survival in patients with SCLC. Finally, we demonstrate that combined statin and chemotherapy treatment resulted in durable responses in three patients with SCLC who relapsed from first-line chemotherapy. Collectively, these data uncover the MVA-GGPP pathway as a metabolic vulnerability in SCLC and identify statins as a potentially effective treatment to overcome chemoresistance.
PMID: 35449308
ISSN: 2662-1347
CID: 5218552

Ontogeny and Vulnerabilities of Drug-Tolerant Persisters in HER2+ Breast Cancer

Chang, Chewei Anderson; Jen, Jayu; Jiang, Shaowen; Sayad, Azin; Mer, Arvind Singh; Brown, Kevin R; Nixon, Allison M L; Dhabaria, Avantika; Tang, Kwan Ho; Venet, David; Sotiriou, Christos; Deng, Jiehui; Wong, Kwok-Kin; Adams, Sylvia; Meyn, Peter; Heguy, Adriana; Skok, Jane A; Tsirigos, Aristotelis; Ueberheide, Beatrix; Moffat, Jason; Singh, Abhyudai; Haibe-Kains, Benjamin; Khodadadi-Jamayran, Alireza; Neel, Benjamin G
Resistance to targeted therapies is an important clinical problem in HER2-positive (HER2+) breast cancer. "Drug-tolerant persisters" (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in other malignancies, but DTPs following HER2 TKI exposure have not been well characterized. We found that HER2 TKIs evoke DTPs with a luminal-like or a mesenchymal-like transcriptome. Lentiviral barcoding/single cell RNA-sequencing reveal that HER2+ breast cancer cells cycle stochastically through a "pre-DTP" state, characterized by a G0-like expression signature and enriched for diapause and/or senescence genes. Trajectory analysis/cell sorting show that pre-DTPs preferentially yield DTPs upon HER2 TKI exposure. Cells with similar transcriptomes are present in HER2+ breast tumors and are associated with poor TKI response. Finally, biochemical experiments indicate that luminal-like DTPs survive via estrogen receptor-dependent induction of SGK3, leading to rewiring of the PI3K/AKT/mTORC1 pathway to enable AKT-independent mTORC1 activation.
PMID: 34911733
ISSN: 2159-8290
CID: 5085072

Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Zhou, Jin; Wu, Zhong; Zhang, Zhouwei; Goss, Louisa; McFarland, James; Nagaraja, Ankur; Xie, Yingtian; Gu, Shengqing; Peng, Ke; Zeng, Yong; Zhang, Xiaoyang; Long, Henry; Nakagawa, Hiroshi; Rustgi, Anil; Diehl, J Alan; Meyerson, Matthew; Wong, Kwok-Kin; Bass, Adam
OBJECTIVE:Oesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition. DESIGN/METHODS:We combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer. RESULTS:We identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC. CONCLUSION/CONCLUSIONS:These results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.
PMID: 33789967
ISSN: 1468-3288
CID: 5148152