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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

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

Loss of TSC1/TSC2 sensitizes immune checkpoint blockade in non-small cell lung cancer

Huang, Qingyuan; Li, Fei; Hu, Hai; Fang, Zhaoyuan; Gao, Zhendong; Xia, Guozhan; Ng, Wai-Lung; Khodadadi-Jamayran, Alireza; Chen, Ting; Deng, Jiehui; Zhang, Hua; Almonte, Christina; Labbe, Kristen; Han, Han; Geng, Ke; Tang, Sittinon; Freeman, Gordon J; Li, Yuan; Chen, Haiquan; Wong, Kwok-Kin
Tuberous sclerosis complex subunit 1 (TSC1) and 2 (TSC2) are frequently mutated in non-small cell lung cancer (NSCLC), however, their effects on antitumor immunity remained unexplored. A CRISPR screening in murine KrasG12D
PMID: 35119931
ISSN: 2375-2548
CID: 5150752

Combined Inhibition of SHP2 and CXCR1/2 Promotes Anti-Tumor T Cell Response in NSCLC

Tang, Kwan Ho; Li, Shuai; Khodadadi-Jamayran, Alireza; Jen, Jayu; Han, Han; Guidry, Kayla; Chen, Ting; Hao, Yuan; Fedele, Carmine; Zebala, John A; Maeda, Dean Y; Christensen, James G; Olson, Peter; Athanas, Argus; Loomis, Cynthia A; Tsirigos, Aristotelis; Wong, Kwok-Kin; Neel, Benjamin G
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with over-activation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non-small cell lung cancer (NSCLC). However, treatment also increased intratumor gMDSCs via tumor-intrinsic, NF-kB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C-inhibitor trials. Combined SHP2(SHP099)/CXCR1/2(SX682) inhibition depleted a specific cluster of S100a8/9high gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in NSCLC patients.
PMID: 34353854
ISSN: 2159-8290
CID: 4969352

Targeting the Atf7ip-Setdb1 Complex Augments Antitumor Immunity by Boosting Tumor Immunogenicity

Hu, Hai; Khodadadi-Jamayran, Alireza; Dolgalev, Igor; Cho, Hyunwoo; Badri, Sana; Chiriboga, Luis A; Zeck, Briana; Lopez De Rodas Gregorio, Miguel; Dowling, Catríona M; Labbe, Kristen; Deng, Jiehui; Chen, Ting; Zhang, Hua; Zappile, Paul; Chen, Ze; Ueberheide, Beatrix; Karatza, Angeliki; Han, Han; Ranieri, Michela; Tang, Sittinon; Jour, George; Osman, Iman; Sucker, Antje; Schadendorf, Dirk; Tsirigos, Aristotelis; Schalper, Kurt A; Velcheti, Vamsidhar; Huang, Hsin-Yi; Jin, Yujuan; Ji, Hongbin; Poirier, John T; Li, Fei; Wong, Kwok-Kin
Substantial progress has been made in understanding how tumors escape immune surveillance. However, few measures to counteract tumor immune evasion have been developed. Suppression of tumor antigen expression is a common adaptive mechanism that cancers use to evade detection and destruction by the immune system. Epigenetic modifications play a critical role in various aspects of immune invasion, including the regulation of tumor antigen expression. To identify epigenetic regulators of tumor antigen expression, we established a transplantable syngeneic tumor model of immune escape with silenced antigen expression and used this system as a platform for a CRISPR-Cas9 suppressor screen for genes encoding epigenetic modifiers. We found that disruption of the genes encoding either of the chromatin modifiers activating transcription factor 7-interacting protein (Atf7ip) or its interacting partner SET domain bifurcated histone lysine methyltransferase 1 (Setdb1) in tumor cells restored tumor antigen expression. This resulted in augmented tumor immunogenicity concomitant with elevated endogenous retroviral (ERV) antigens and mRNA intron retention. ERV disinhibition was associated with a robust type I interferon response and increased T-cell infiltration, leading to rejection of cells lacking intact Atf7ip or Setdb1. ATF7IP or SETDB1 expression inversely correlated with antigen processing and presentation pathways, interferon signaling, and T-cell infiltration and cytotoxicity in human cancers. Our results provide a rationale for targeting Atf7ip or Setdb1 in cancer immunotherapy.
PMID: 34462284
ISSN: 2326-6074
CID: 5061142

Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

Han, Han; Li, Shuai; Chen, Ting; Fitzgerald, Michael; Liu, Shengwu; Peng, Chengwei; Tang, Kwan Ho; Cao, Shougen; Chouitar, Johara; Wu, Jiansheng; Peng, David; Deng, Jiehui; Gao, Zhendong; Baker, Theresa E; Li, Fei; Zhang, Hua; Pan, Yuanwang; Ding, Hailin; Hu, Hai; Pyon, Val; Thakurdin, Cassandra; Papadopoulos, Eleni; Tang, Sittinon; Gonzalvez, Francois; Chen, Haiquan; Rivera, Victor M; Brake, Rachael; Vincent, Sylvie; Wong, Kwok-Kin
No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion-mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion-mutant lung adenocarcinoma patients. SIGNIFICANCE: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion-mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
PMID: 34380634
ISSN: 1538-7445
CID: 5060992

ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer

Deng, Jiehui; Thennavan, Aatish; Dolgalev, Igor; Chen, Ting; Li, Jie; Marzio, Antonio; Poirier, John T; Peng, David; Bulatovic, Mirna; Mukhopadhyay, Subhadip; Silver, Heather; Papadopoulos, Eleni; Pyon, Val; Thakurdin, Cassandra; Han, Han; Li, Fei; Li, Shuai; Ding, Hailin; Hu, Hai; Pan, Yuanwang; Weerasekara, Vajira; Jiang, Baishan; Wang, Eric S; Ahearn, Ian; Philips, Mark; Papagiannakopoulos, Thales; Tsirigos, Aristotelis; Rothenberg, Eli; Gainor, Justin; Freeman, Gordon J; Rudin, Charles M; Gray, Nathanael S; Hammerman, Peter S; Pagano, Michele; Heymach, John V; Perou, Charles M; Bardeesy, Nabeel; Wong, Kwok-Kin
PMID: 34142094
ISSN: 2662-1347
CID: 4917722

SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling

Fedele, Carmine; Li, Shuai; Teng, Kai Wen; Foster, Connor J R; Peng, David; Ran, Hao; Mita, Paolo; Geer, Mitchell J; Hattori, Takamitsu; Koide, Akiko; Wang, Yubao; Tang, Kwan Ho; Leinwand, Joshua; Wang, Wei; Diskin, Brian; Deng, Jiehui; Chen, Ting; Dolgalev, Igor; Ozerdem, Ugur; Miller, George; Koide, Shohei; Wong, Kwok-Kin; Neel, Benjamin G
KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site-specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
PMID: 33045063
ISSN: 1540-9538
CID: 4632492

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer

Wang, Wei; Marinis, Jill M; Beal, Allison M; Savadkar, Shivraj; Wu, Yue; Khan, Mohammed; Taunk, Pardeep S; Wu, Nan; Su, Wenyu; Wu, Jingjing; Ahsan, Aarif; Kurz, Emma; Chen, Ting; Yaboh, Inedouye; Li, Fei; Gutierrez, Johana; Diskin, Brian; Hundeyin, Mautin; Reilly, Michael; Lich, John D; Harris, Philip A; Mahajan, Mukesh K; Thorpe, James H; Nassau, Pamela; Mosley, Julie E; Leinwand, Joshua; Kochen Rossi, Juan A; Mishra, Ankita; Aykut, Berk; Glacken, Michael; Ochi, Atsuo; Verma, Narendra; Kim, Jacqueline I; Vasudevaraja, Varshini; Adeegbe, Dennis; Almonte, Christina; Bagdatlioglu, Ece; Cohen, Deirdre J; Wong, Kwok-Kin; Bertin, John; Miller, George
PMID: 33049209
ISSN: 1878-3686
CID: 4632692

Epigenetic CRISPR screens identify Npm1 as a therapeutic vulnerability in non-small cell lung cancer

Li, Fei; Ng, Wai-Lung; Luster, Troy A; Hu, Hai; Sviderskiy, Vladislav O; Dowling, Catríona M; Hollinshead, Kate E R; Zouitine, Paula; Zhang, Hua; Huang, Qingyuan; Ranieri, Michela; Wang, Wei; Fang, Zhaoyuan; Chen, Ting; Deng, Jiehui; Zhao, Kai; So, Hon-Cheong; Khodadadi-Jamayran, Alireza; Xu, Mousheng; Karatza, Angeliki; Pyon, Val; Li, Shuai; Pan, Yuanwang; Labbe, Kristen; Almonte, Christina; Poirier, John T; Miller, George; Possemato, Richard; Qi, Jun; Wong, Kwok-Kin
Despite advancements in treatment options, the overall cure and survival rates for non-small cell lung cancers (NSCLC) remain low. While small-molecule inhibitors of epigenetic regulators have recently emerged as promising cancer therapeutics, their application in patients with NSCLC is limited. To exploit epigenetic regulators as novel therapeutic targets in NSCLC, we performed pooled epigenome-wide CRISPR knockout screens in vitro and in vivo and identified the histone chaperone nucleophosmin 1 (NPM1) as a potential therapeutic target. Genetic ablation of Npm1 significantly attenuated tumor progression in vitro and in vivo. Furthermore, KRAS-mutant cancer cells were more addicted to NPM1 expression. Genetic ablation of Npm1 rewired the balance of metabolism in cancer cells from predominant aerobic glycolysis to oxidative phosphorylation and reduced the population of tumor-propagating cells. Overall, our results support NPM1 as a therapeutic vulnerability in NSCLC.
PMID: 32646968
ISSN: 1538-7445
CID: 4518022