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KRAS AND “checkpoint inhibitors”

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https://www.readbyqxmd.com/read/30231342/molecular-subtypes-and-the-evolution-of-treatment-decisions-in-metastatic-colorectal-cancer
#1
Rodrigo Dienstmann, Ramon Salazar, Josep Tabernero
Colorectal cancer (CRC) has clinically relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics, and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations define a population refractory to epidermal growth factor receptor monoclonal antibodies, BRAFV600E mutations associate with poor outcomes under standard therapies and response to targeted inhibitors in combinations, and HER2 amplifications confer unique sensitivity to double HER2 blockade...
May 23, 2018: American Society of Clinical Oncology Educational Book
https://www.readbyqxmd.com/read/30113497/comparative-analysis-of-immune-checkpoint-inhibitors-and-chemotherapy-in-the-treatment-of-advanced-non-small-cell-lung-cancer-a-meta-analysis-of-randomized-controlled-trials
#2
REVIEW
Muhammad Khan, Jie Lin, Guixiang Liao, Yunhong Tian, Yingying Liang, Rong Li, Mengzhong Liu, Yawei Yuan
BACKGROUND: Recently, immune checkpoint inhibitors have shown survival advantage over chemotherapy in the treatment of advanced non-small cell lung cancer (NSCLC). This meta-analysis was conducted to gather and analyze the available evidence (Evidence level I; Randomized Controlled Trials) comparing efficacy and safety of anti-programmed cell death-1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies and chemotherapy in the treatment of advanced NSCLC. METHODS: A search strategy was devised to identify the randomized controlled trials (RCTs) using electronic databases of PubMed, Cochrane Library, and Web of Science...
August 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/30087114/bet-bromodomain-inhibition-cooperates-with-pd-1-blockade-to-facilitate-antitumor-response-in-kras-mutant-non-small-cell-lung-cancer
#3
Dennis O Adeegbe, Shengwu Liu, Maureen M Hattersley, Michaela Bowden, Chensheng W Zhou, Shuai Li, Raven Vlahos, Michael Grondine, Igor Dolgalev, Elena V Ivanova, Max M Quinn, Peng Gao, Peter S Hammerman, James E Bradner, J Alan Diehl, Anil K Rustgi, Adam J Bass, Aristotelis Tsirigos, Gordon J Freeman, Huawei Chen, Kwok-Kin Wong
KRAS mutation is present in approximately 30% of human lung adenocarcinomas. Although recent advances in targeted therapy have shown great promise, effective targeting of KRAS remains elusive, and concurrent alterations in tumor suppressors render KRAS- mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS -mutant tumors are immunosuppressive mechanisms, such as increased presence of suppressive regulatory T cells (Treg) in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells...
October 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/30006421/response-to-checkpoint-inhibitor-therapy-in-advanced-classic-kaposi-sarcoma-a-case-report-and-immunogenomic-study
#4
James Saller, Christine M Walko, Sherri Z Millis, Evita Henderson-Jackson, Rikesh Makanji, Andrew S Brohl
Kaposi sarcoma (KS) is an uncommon angioproliferative malignancy that is associated with human herpesvirus 8. Although there has been recent enthusiasm for evaluating immune checkpoint inhibition as a therapeutic option for viral-associated tumors, the clinical utility in this disease is currently unknown. We report a case of advanced classic KS refractory to multiple lines of chemotherapy that experienced a partial response to anti-PD-1 therapy. Comprehensive molecular profiling was performed on a diagnostic tumor biopsy sample...
July 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29997286/immune-reprogramming-via-pd-1-inhibition-enhances-early-stage-lung-cancer-survival
#5
Geoffrey J Markowitz, Lauren S Havel, Michael Jp Crowley, Yi Ban, Sharrell B Lee, Jennifer S Thalappillil, Navneet Narula, Bhavneet Bhinder, Olivier Elemento, Stephen Tc Wong, Dingcheng Gao, Nasser K Altorki, Vivek Mittal
Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression...
July 12, 2018: JCI Insight
https://www.readbyqxmd.com/read/29900052/time-tumor-immunity-in-the-microenvironment-classification-based-on-tumor-cd274-pd-l1-expression-status-and-tumor-infiltrating-lymphocytes-in-colorectal-carcinomas
#6
Tsuyoshi Hamada, Thing Rinda Soong, Yohei Masugi, Keisuke Kosumi, Jonathan A Nowak, Annacarolina da Silva, Xinmeng Jasmine Mu, Tyler S Twombly, Hideo Koh, Juhong Yang, Mingyang Song, Li Liu, Mancang Gu, Yan Shi, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Sachet A Shukla, Catherine J Wu, Levi A Garraway, Xuehong Zhang, Kana Wu, Jeffrey A Meyerhardt, Andrew T Chan, Jonathan N Glickman, Scott J Rodig, Gordon J Freeman, Charles S Fuchs, Reiko Nishihara, Marios Giannakis, Shuji Ogino
Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 ( PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274 low /TILabsent ; TIME 2, CD274 high /TILpresent ; TIME 3, CD274 low /TILpresent ; and TIME 4, CD274 high /TILabsent )...
2018: Oncoimmunology
https://www.readbyqxmd.com/read/29571084/comprehensive-analysis-of-cancers-of-unknown-primary-for-the-biomarkers-of-response-to-immune-checkpoint-blockade-therapy
#7
Zoran Gatalica, Joanne Xiu, Jeff Swensen, Semir Vranic
BACKGROUND: Cancer of unknown primary (CUP) accounts for approximately 3% of all malignancies. Avoiding immune destruction is a major cancer characteristic and therapies aimed at immune checkpoint blockade are in use for several specific cancer types. A comprehensive survey of predictive biomarkers to immune checkpoint blockade in CUP were explored in this study. METHODS: About 389 cases of CUP were analysed for mutations in 592 genes and 52 gene fusions using a massively parallel DNA sequencing platform (next-generation sequencing [NGS])...
May 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29568386/correlation-of-met-gene-amplification-and-tp53-mutation-with-pd-l1-expression-in-non-small-cell-lung-cancer
#8
Maher Albitar, Sucha Sudarsanam, Wanlong Ma, Shiping Jiang, Wayne Chen, Vincent Funari, Forrest Blocker, Sally Agersborg
Background: The role of MET amplification in lung cancer, particularly in relation to checkpoint inhibition and EGFR WT, has not been fully explored. In this study, we correlated PD-L1 expression with MET amplification and EGFR , KRAS , or TP53 mutation in primary lung cancer. Methods: In this retrospective study, tissue collected from 471 various tumors, including 397 lung cancers, was tested for MET amplification by FISH with a MET /centromere probe. PD-L1 expression was evaluated using clone SP142 and standard immunohistochemistry, and TP53 , KRAS , and EGFR mutations were tested using next generation sequencing...
March 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29438172/gastric-carcinomas-with-lymphoid-stroma-an-evaluation-of-the-histopathologic-and-molecular-features
#9
Erika Hissong, Girish Ramrattan, Pan Zhang, Xi Kathy Zhou, Gloria Young, David S Klimstra, Jinru Shia, Helen Fernandes, Rhonda K Yantiss
Gastric carcinoma with lymphoid stroma is an uncommon variant enriched for mutually exclusive Epstein-Barr virus (EBV) positivity and mismatch repair (MMR) deficiency. We performed this study to evaluate molecular alterations in this morphologically homogeneous subtype and compare them with 295 conventional gastric cancers analyzed in The Cancer Genome Atlas study. We identified 31 study cases and subjected them to in situ hybridization for EBV-encoded RNAs and assessment for MMR status. Immunostains for PD-L1, β-catenin, and HER2 were performed; extracted DNA was sequenced with a Comprehensive Cancer Panel...
April 2018: American Journal of Surgical Pathology
https://www.readbyqxmd.com/read/29339375/tusc2-immunogene-therapy-synergizes-with-anti-pd-1-through-enhanced-proliferation-and-infiltration-of-natural-killer-cells-in-syngeneic-kras-mutant-mouse-lung-cancer-models
#10
Ismail M Meraz, Mourad Majidi, Xiaobo Cao, Heather Lin, Lerong Li, Jing Wang, Veera Baladandayuthapani, David Rice, Boris Sepesi, Lin Ji, Jack A Roth
Expression of the multikinase inhibitor encoded by the tumor suppressor gene TUSC2 (also known as FUS1 ) is lost or decreased in non-small cell lung carcinoma (NSCLC). TUSC2 delivered systemically by nanovesicles has mediated tumor regression in clinical trials. Because of the role of TUSC2 in regulating immune cells, we assessed TUSC2 efficacy on antitumor immune responses alone and in combination with anti-PD-1 in two Kras -mutant syngeneic mouse lung cancer models. TUSC2 alone significantly reduced tumor growth and prolonged survival compared with anti-PD-1...
February 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29145973/tak-ing-aim-at-chemoresistance-the-emerging-role-of-map3k7-as-a-target-for-cancer-therapy
#11
Raffaela Santoro, Carmine Carbone, Geny Piro, Paul J Chiao, Davide Melisi
Cellular drug resistance remains the main obstacle to the clinical efficacy of cancer chemotherapy. Alterations in key pathways regulating cell cycle checkpoints, apoptosis and Epithelial to Mesenchymal Transition (EMT), such as the Mitogen-activated protein kinase (MAPK) pathway, appear to be closely associated to cancer chemoresistance. Transforming growth factor-β (TGF-β)- activated kinase 1 (TAK1, also known as MAP3K7) is a serine/threonine kinase in the mitogen-activated protein kinase (MAP3K) family...
November 2017: Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
https://www.readbyqxmd.com/read/29138515/targeting-a-non-oncogene-addiction-to-the-atr-chk1-axis-for-the-treatment-of-small-cell-lung-cancer
#12
Fabian Doerr, Julie George, Anna Schmitt, Filippo Beleggia, Tim Rehkämper, Sarah Hermann, Vonn Walter, Jean-Philip Weber, Roman K Thomas, Maike Wittersheim, Reinhard Büttner, Thorsten Persigehl, H Christian Reinhardt
Small cell lung cancer (SCLC) is a difficult to treat subtype of lung cancer. One of the hallmarks of SCLC is its almost uniform chemotherapy sensitivity. However, chemotherapy response is typically transient and patients frequently succumb to SCLC within a year following diagnosis. We performed a transcriptome analysis of the major human lung cancer entities. We show a significant overexpression of genes involved in the DNA damage response, specifically in SCLC. Particularly CHEK1, which encodes for the cell cycle checkpoint kinase CHK1, is significantly overexpressed in SCLC, compared to lung adenocarcinoma...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29089357/effects-of-co-occurring-genomic-alterations-on-outcomes-in-patients-with-kras-mutant-non-small-cell-lung-cancer
#13
Kathryn C Arbour, Emmett Jordan, Hyunjae Ryan Kim, Jordan Dienstag, Helena A Yu, Francisco Sanchez-Vega, Piro Lito, Michael Berger, David B Solit, Matthew Hellmann, Mark G Kris, Charles M Rudin, Ai Ni, Maria Arcila, Marc Ladanyi, Gregory J Riely
Purpose: KRAS mutations occur in approximately 25% of patients with non-small cell lung cancer (NSCLC). Despite the uniform presence of KRAS mutations, patients with KRAS -mutant NSCLC can have a heterogeneous clinical course. As the pattern of co-occurring mutations may describe different biological subsets of patients with KRAS -mutant lung adenocarcinoma, we explored the effects of co-occurring mutations on patient outcomes and response to therapy. Experimental Design: We identified patients with advanced KRAS -mutant NSCLC and evaluated the most common co-occurring genomic alterations...
January 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29081842/treating-kras-mutant-nsclc-latest-evidence-and-clinical-consequences
#14
REVIEW
Pilar Garrido, María Eugenia Olmedo, Ana Gómez, Luis Paz Ares, Fernando López-Ríos, Juan Manuel Rosa-Rosa, José Palacios
KRAS mutations represent one of the most prevalent oncogenic driver mutations in non-small cell lung cancer (NSCLC). For many years we have unsuccessfully addressed KRAS mutation as a unique disease. The recent widespread use of comprehensive genomic profiling has identified different subgroups with prognostic implications. Moreover, recent data recognizing the distinct biology and therapeutic vulnerabilities of different KRAS subgroups have allowed us to explore different treatment approaches. Small molecules that selectively inhibit KRAS G12C or use of immune checkpoint inhibitors based on co-mutation status are some examples which anticipate that personalized treatment for this challenging disease is finally on the horizon...
September 2017: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29074606/low-pd-1-expression-in-cytotoxic-cd8-tumor-infiltrating-lymphocytes-confers-an-immune-privileged-tissue-microenvironment-in-nsclc-with-a-prognostic-and-predictive-value
#15
Giulia Mazzaschi, Denise Madeddu, Angela Falco, Giovanni Bocchialini, Matteo Goldoni, Francesco Sogni, Giovanna Armani, Costanza Annamaria Lagrasta, Bruno Lorusso, Chiara Mangiaracina, Rocchina Vilella, Caterina Frati, Roberta Alfieri, Luca Ampollini, Michele Veneziani, Enrico Maria Silini, Andrea Ardizzoni, Konrad Urbanek, Franco Aversa, Federico Quaini, Marcello Tiseo
Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in non-small cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed. Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed...
January 15, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28978051/mutational-status-of-tp53-defines-the-efficacy-of-wee1-inhibitor-azd1775-in-kras-mutant-non-small-cell-lung-cancer
#16
Bo Mi Ku, Yeon-Hee Bae, Jiae Koh, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn
KRAS is frequently mutated in non-small cell lung cancer (NSCLC). However, direct targeting of KRAS has proven to be challenging, and inhibition of KRAS effectors has resulted in limited clinical efficacy. Wee1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancers. Inhibition of Wee1 exerts anticancer effects as a monotherapy or in combination with DNA-damaging agents when cancer cells harbor TP53 mutations. However, its role in KRAS-mutant NSCLC, especially as a single agent, has not been explored...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28807001/the-mek-inhibitor-selumetinib-complements-ctla-4-blockade-by-reprogramming-the-tumor-immune-microenvironment
#17
Edmund Poon, Stefanie Mullins, Amanda Watkins, Geoffrey S Williams, Jens-Oliver Koopmann, Gianfranco Di Genova, Marie Cumberbatch, Margaret Veldman-Jones, Shaun E Grosskurth, Vasu Sah, Alwin Schuller, Corrine Reimer, Simon J Dovedi, Paul D Smith, Ross Stewart, Robert W Wilkinson
BACKGROUND: T-cell checkpoint blockade and MEK inhibitor combinations are under clinical investigation. Despite progress elucidating the immuno-modulatory effects of MEK inhibitors as standalone therapies, the impact of MEK inhibition on the activity of T-cell checkpoint inhibitors remains incompletely understood. Here we sought to characterize the combined effects of MEK inhibition and anti-CTLA-4 mAb (anti-CTLA-4) therapy, examining effects on both T-cells and tumor microenvironment (TME)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28775144/a-bifunctional-mapk-pi3k-antagonist-for-inhibition-of-tumor-growth-and-metastasis
#18
Stefanie Galbán, April A Apfelbaum, Carlos Espinoza, Kevin Heist, Henry Haley, Karan Bedi, Mats Ljungman, Craig J Galbán, Gary D Luker, Marcian Van Dort, Brian D Ross
Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN-mutant melanomas...
November 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28754670/gemcitabine-and-chk1-inhibitor-azd7762-synergistically-suppress-the-growth-of-lkb1-deficient-lung-adenocarcinoma
#19
Yan Liu, Yuyang Li, Xiaoen Wang, Feiyang Liu, Peng Gao, Max M Quinn, Fei Li, Ashley A Merlino, Cyril Benes, Qingsong Liu, Nathanael S Gray, Kwok-Kin Wong
Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1 -induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models...
September 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28676214/dna-mismatch-repair-deficiency-in-surgically-resected-lung-adenocarcinoma-microsatellite-instability-analysis-using-the-promega-panel
#20
Kazuya Takamochi, Fumiyuki Takahashi, Yoshiyuki Suehara, Eiichi Sato, Shinji Kohsaka, Takuo Hayashi, Shigehisa Kitano, Toshihide Uneno, Shinya Kojima, Kengo Takeuchi, Hiroyuki Mano, Kenji Suzuki
OBJECTIVES: DNA mismatch repair (MMR) deficiency has recently received increasing attention as a significant biomarker to predict the treatment effect of immune checkpoint inhibitors for various malignant neoplasms. To evaluate MMR status, we analyzed the microsatellite instability (MSI) of lung adenocarcinomas. MATERIALS AND METHODS: Frozen tissues of lung adenocarcinoma and corresponding normal lung were obtained from 341 patients, including 141 with tumors harboring driver gene alterations (50 EGFR gene mutations, 50 KRAS gene mutations, 21 ALK fusions, 10 ROS1 fusions, and 10 RET fusions) and 200 with pan-negative tumors (100 never- or light-smokers and 100 heavy-smokers), who were surgically treated between 2007 and 2015...
August 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
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