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Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation

Tan, Xiaohong; Tong, Lu; Li, Lin; Xu, Jinjin; Xie, Shaofang; Ji, Lei; Fu, Junjiang; Liu, Qingwu; Shen, Shihui; Liu, Yun; Xiao, Yanhui; Gao, Feiran; Moses, Robb E; Bardeesy, Nabeel; Wang, Yanxiao; Zhang, Jishuai; Tang, Longying; Li, Lei; Wong, Kwok-Kin; Song, Dianwen; Yang, Xiao; Liu, Jian; Li, Xiaotao
SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3'UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
PMID: 34381046
ISSN: 2041-1723
CID: 5004402

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

Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non-Small Cell Lung Cancer

Gonzalvez, Francois; Vincent, Sylvie; Baker, Theresa E; Gould, Alexandra E; Li, Shuai; Wardwell, Scott D; Nadworny, Sara; Ning, Yaoyu; Zhang, Sen; Huang, Wei-Sheng; Hu, Yongbo; Li, Feng; Greenfield, Matthew T; Zech, Stephan G; Das, Biplab; Narasimhan, Narayana I; Clackson, Tim; Dalgarno, David; Shakespeare, William C; Fitzgerald, Michael; Chouitar, Johara; Griffin, Robert J; Liu, Shengwu; Wong, Kwok-Kin; Zhu, Xiaotian; Rivera, Victor M
Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.
PMID: 33632773
ISSN: 2159-8290
CID: 4974722

The KRASG12C Inhibitor MRTX849 Reconditions the Tumor Immune Microenvironment and Sensitizes Tumors to Checkpoint Inhibitor Therapy

Briere, David M; Li, Shuai; Calinisan, Andrew; Sudhakar, Niranjan; Aranda, Ruth; Hargis, Lauren; Peng, David H; Deng, Jiehui; Engstrom, Lars D; Hallin, Jill; Gatto, Sole; Fernandez-Banet, Julio; Pavlicek, Adam; Wong, Kwok-Kin; Christensen, James G; Olson, Peter
KRASG12C inhibitors, including MRTX849, are promising treatment options for KRAS-mutant non-small cell lung cancer (NSCLC). PD-1 inhibitors are approved in NSCLC; however, strategies to enhance checkpoint inhibitor therapy (CIT) are needed. KRASG12C mutations are smoking-associated transversion mutations associated with high tumor mutation burden (TMB), PD-L1 positivity and an immunosuppressive tumor microenvironment. To evaluate the potential of MRTX849 to augment CIT, its impact on immune signaling and response to CIT was evaluated. In human tumor xenograft models, MRTX849 increased MHC class I protein expression and decreased RNA and/or plasma protein levels of immunosuppressive factors. In a KRASG12C-mutant CT26 syngeneic mouse model, MRTX849 decreased intratumoral myeloid-derived suppressor cells (MDSCs) and increased M1-polarized macrophages, dendritic cells, CD4+ and CD8+ T cells. Similar results were observed in lung KrasG12C-mutant syngeneic and a genetically engineered mouse (GEM) model. In the CT26 KrasG12C model, MRTX849 demonstrated marked tumor regression when tumors were established in immune-competent BALB/c mice; however, the effect was diminished when tumors were grown in T-cell deficient nu/nu mice. Tumors progressed following anti-PD-1 or MRTX849 single agent treatment in immune-competent mice; however, combination treatment demonstrated durable, complete responses (CRs). Tumors did not re-establish in the same mice that exhibited durable CRs when re-challenged with tumor cell inoculum, demonstrating these mice developed adaptive anti-tumor immunity. In a GEM model, treatment with MRTX849 plus anti-PD-1 led to increased progression-free survival compared to either single agent alone. These data demonstrate KRAS inhibition reverses an immunosuppressive tumor microenvironment and sensitizes tumors to CIT through multiple mechanisms.
PMID: 33722854
ISSN: 1538-8514
CID: 4837732

Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence

Wu, Zhong; Zhou, Jin; Zhang, Xiaoyang; Zhang, Zhouwei; Xie, Yingtian; Liu, Jie Bin; Ho, Zandra V; Panda, Arpit; Qiu, Xintao; Cejas, Paloma; Cañadas, Israel; Akarca, Fahire Goknur; McFarland, James M; Nagaraja, Ankur K; Goss, Louisa B; Kesten, Nikolas; Si, Longlong; Lim, Klothilda; Liu, Yanli; Zhang, Yanxi; Baek, Ji Yeon; Liu, Yang; Patil, Deepa T; Katz, Jonathan P; Hai, Josephine; Bao, Chunyang; Stachler, Matthew; Qi, Jun; Ishizuka, Jeffrey J; Nakagawa, Hiroshi; Rustgi, Anil K; Wong, Kwok-Kin; Meyerson, Matthew; Barbie, David A; Brown, Myles; Long, Henry; Bass, Adam J
Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2-induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5, oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3. Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities.
PMID: 33972779
ISSN: 1546-1718
CID: 4868182

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

Clinical Characteristics and Outcomes of COVID-19-Infected Cancer Patients: A Systematic Review and Meta-Analysis

Zhang, Hua; Han, Han; He, Tianhui; Labbe, Kristen E; Hernandez, Adrian V; Chen, Haiquan; Velcheti, Vamsidhar; Stebbing, Justin; Wong, Kwok-Kin
BACKGROUND:Previous studies have indicated Coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate. METHODS:We conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariate logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes. RESULTS:We included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the UK and Europe, followed by the USA and Canada (35.7%) and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (odds ratio [OR] = 3.57; 95% CI = 1.80 to 7.06), male (OR = 2.10; 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00; 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariate analysis, only age greater than 65 years (OR = 3.16; 95% CI = 1.45 to 6.88) and being male (OR = 2.29; 95% CI = 1.07 to 4.87) were associated with increased risk of severe events. CONCLUSION/CONCLUSIONS:Our analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate when compared with that of COVID-19 patients without cancer. Age and gender appear to be risk factors associated with a poorer prognosis.
PMID: 33136163
ISSN: 1460-2105
CID: 4655872

Recent advances in preclinical models for lung squamous cell carcinoma

Pan, Yuanwang; Han, Han; Labbe, Kristen E; Zhang, Hua; Wong, Kwok-Kin
Lung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer with limited treatment options. Previous studies have elucidated the complex genetic landscape of LUSC and revealed multiple altered genes and pathways. However, in stark contrast to lung adenocarcinoma, few targetable driver mutations have been established so far and targeted therapies for LUSC remain unsuccessful. Immunotherapy has revolutionized LUSC treatment and is currently approved as the new standard of care. To gain a better understanding of the LUSC biology, improved modeling systems are urgently needed. Preclinical models, particularly those mimicking human disease with an intact tumor immune microenvironment, are an invaluable tool to study cancer development and evaluate new therapeutic targets. Here, we discuss recent advances in LUSC preclinical models, with a focus on genetically engineered mouse models (GEMMs) and organoids, in the context of evolving precision medicine and immunotherapy.
PMID: 33707749
ISSN: 1476-5594
CID: 4819622

Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target

Le, Xiuning; Negrao, Marcelo V; Reuben, Alexandre; Federico, Lorenzo; Diao, Lixia; McGrail, Daniel; Nilsson, Monique; Robichaux, Jacqulyne; Munoz, Irene Guijarro; Patel, Sonia; Elamin, Yasir; Fan, You-Hong; Lee, Won-Chul; Parra, Edwin; Solis Soto, Luisa Maren; Chen, Runzhe; Li, Jun; Karpinets, Tatiana; Khairullah, Roohussaba; Kadara, Humam; Behrens, Carmen; Sepesi, Boris; Wang, Ruiping; Zhu, Mingrui; Wang, Linghua; Vaporciyan, Ara; Roth, Jack; Swisher, Stephen; Haymaker, Cara; Zhang, Jianhua; Wang, Jing; Wong, Kwok-Kin; Byers, Lauren A; Bernatchez, Chantale; Zhang, Jianjun; Wistuba, Ignacio I; Gibbons, Don L; Akbay, Esra A; Heymach, John V
INTRODUCTION/BACKGROUND:Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood. METHODS:We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response. RESULTS:EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth. CONCLUSIONS:Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
PMID: 33388477
ISSN: 1556-1380
CID: 4835272

Response to Cottu, Bozec, Basse, and Paoletti

Zhang, Hua; Han, Han; He, Tianhui; Labbe, Kristen E; Hernandez, Adrian V; Chen, Haiquan; Velcheti, Vamsidhar; Stebbing, Justin; Wong, Kwok-Kin
PMID: 33404597
ISSN: 1460-2105
CID: 4738932