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  1. Article: Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.

    Habowski, Amber N / Budagavi, Deepthi P / Scherer, Sandra D / Aurora, Arin B / Caligiuri, Giuseppina / Flynn, William F / Langer, Ellen M / Brody, Jonathan R / Sears, Rosalie C / Foggetti, Giorgia / Arnal Estape, Anna / Nguyen, Don X / Politi, Katerina A / Shen, Xiling / Hsu, David S / Peehl, Donna M / Kurhanewicz, John / Sriram, Renuka / Suarez, Milagros /
    Xiao, Sophie / Du, Yuchen / Li, Xiao-Nan / Navone, Nora M / Labanca, Estefania / Willey, Christopher D

    Cancers

    2024  Volume 16, Issue 3

    Abstract: For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of ...

    Abstract For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics. Based on collective experience from the consortium groups, we provide insight regarding PDMCs established both in vitro and in vivo, with a focus on practical matters related to developing and maintaining key cancer models through a series of vignettes. Although every model has the potential to offer valuable insights, the choice of the right model should be guided by the research question. However, recognizing the inherent constraints in each model is crucial. Our objective here is to delineate the strengths and limitations of each model as established by individual vignettes. Further advances in PDMCs and the development of novel model systems will enable us to better understand human biology and improve the study of human pathology in the lab.
    Language English
    Publishing date 2024-01-29
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers16030565
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer.

    de Miguel, Fernando J / Gentile, Claudia / Feng, William W / Silva, Shannon J / Sankar, Akshay / Exposito, Francisco / Cai, Wesley L / Melnick, Mary Ann / Robles-Oteiza, Camila / Hinkley, Madeline M / Tsai, Jeanelle A / Hartley, Antja-Voy / Wei, Jin / Wurtz, Anna / Li, Fangyong / Toki, Maria I / Rimm, David L / Homer, Robert / Wilen, Craig B /
    Xiao, Andrew Z / Qi, Jun / Yan, Qin / Nguyen, Don X / Jänne, Pasi A / Kadoch, Cigall / Politi, Katerina A

    Cancer cell

    2023  Volume 41, Issue 8, Page(s) 1516–1534.e9

    Abstract: Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and ... ...

    Abstract Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.
    MeSH term(s) Animals ; Humans ; Tyrosine Kinase Inhibitors ; Chromatin Assembly and Disassembly ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Chromatin ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; ErbB Receptors/genetics ; Mutation ; Mammals/genetics ; DNA Helicases/genetics ; Nuclear Proteins/genetics ; Transcription Factors/genetics
    Chemical Substances osimertinib (3C06JJ0Z2O) ; Tyrosine Kinase Inhibitors ; Chromatin ; Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; SMARCA4 protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-) ; Nuclear Proteins ; Transcription Factors ; EGFR protein, human (EC 2.7.10.1)
    Language English
    Publishing date 2023-08-03
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2023.07.005
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A path to translation: How 3D patient tumor avatars enable next generation precision oncology.

    Bose, Shree / Barroso, Margarida / Chheda, Milan G / Clevers, Hans / Elez, Elena / Kaochar, Salma / Kopetz, Scott E / Li, Xiao-Nan / Meric-Bernstam, Funda / Meyer, Clifford A / Mou, Haiwei / Naegle, Kristen M / Pera, Martin F / Perova, Zinaida / Politi, Katerina A / Raphael, Benjamin J / Robson, Paul / Sears, Rosalie C / Tabernero, Josep /
    Tuveson, David A / Welm, Alana L / Welm, Bryan E / Willey, Christopher D / Salnikow, Konstantin / Chuang, Jeffrey H / Shen, Xiling

    Cancer cell

    2022  Volume 40, Issue 12, Page(s) 1448–1453

    Abstract: 3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here, we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to realize their potential for clinical decision making. 3D-PTAs ... ...

    Abstract 3D patient tumor avatars (3D-PTAs) hold promise for next-generation precision medicine. Here, we describe the benefits and challenges of 3D-PTA technologies and necessary future steps to realize their potential for clinical decision making. 3D-PTAs require standardization criteria and prospective trials to establish clinical benefits. Innovative trial designs that combine omics and 3D-PTA readouts may lead to more accurate clinical predictors, and an integrated platform that combines diagnostic and therapeutic development will accelerate new treatments for patients with refractory disease.
    MeSH term(s) Humans ; Neoplasms/genetics ; Neoplasms/therapy ; Neoplasms/diagnosis ; Precision Medicine ; Prospective Studies ; Medical Oncology
    Language English
    Publishing date 2022-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2022.09.017
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Update on epidermal growth factor receptor mutations in non-small cell lung cancer.

    Riely, Gregory J / Politi, Katerina A / Miller, Vincent A / Pao, William

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2006  Volume 12, Issue 24, Page(s) 7232–7241

    Abstract: In 2004, several investigators reported that somatic mutations in the epidermal growth factor receptor gene were associated with clinical responses to erlotinib and gefitinib in patients with non-small cell lung cancer. Since then, multiple groups have ... ...

    Abstract In 2004, several investigators reported that somatic mutations in the epidermal growth factor receptor gene were associated with clinical responses to erlotinib and gefitinib in patients with non-small cell lung cancer. Since then, multiple groups have examined the biological properties that such mutations confer as well as the clinical relevance of these mutations in patients with non-small cell lung cancer. Although a tremendous amount of knowledge has been gained in the past 2 years, there remain a number of important epidemiologic, biological, and clinical questions.
    MeSH term(s) Carcinoma, Non-Small-Cell Lung/epidemiology ; Carcinoma, Non-Small-Cell Lung/genetics ; Drug Resistance, Neoplasm ; Gene Duplication ; Gene Frequency ; Humans ; Lung Neoplasms/epidemiology ; Lung Neoplasms/genetics ; Models, Biological ; Mutation/physiology ; Receptor, Epidermal Growth Factor/genetics
    Chemical Substances Receptor, Epidermal Growth Factor (EC 2.7.10.1)
    Language English
    Publishing date 2006-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-06-0658
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.

    Pao, William / Miller, Vincent A / Politi, Katerina A / Riely, Gregory J / Somwar, Romel / Zakowski, Maureen F / Kris, Mark G / Varmus, Harold

    PLoS medicine

    2005  Volume 2, Issue 3, Page(s) e73

    Abstract: Background: Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor ... ...

    Abstract Background: Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib (Iressa) or erlotinib (Tarceva) usually harbor somatic gain-of-function mutations in exons encoding the kinase domain of the epidermal growth factor receptor (EGFR). Despite initial responses, patients eventually progress by unknown mechanisms of "acquired" resistance.
    Methods and findings: We show that in two of five patients with acquired resistance to gefitinib or erlotinib, progressing tumors contain, in addition to a primary drug-sensitive mutation in EGFR, a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain. Tumor cells from a sixth patient with a drug-sensitive EGFR mutation whose tumor progressed on adjuvant gefitinib after complete resection also contained the T790M mutation. This mutation was not detected in untreated tumor samples. Moreover, no tumors with acquired resistance had KRAS mutations, which have been associated with primary resistance to these drugs. Biochemical analyses of transfected cells and growth inhibition studies with lung cancer cell lines demonstrate that the T790M mutation confers resistance to EGFR mutants usually sensitive to either gefitinib or erlotinib. Interestingly, a mutation analogous to T790M has been observed in other kinases with acquired resistance to another kinase inhibitor, imatinib (Gleevec).
    Conclusion: In patients with tumors bearing gefitinib- or erlotinib-sensitive EGFR mutations, resistant subclones containing an additional EGFR mutation emerge in the presence of drug. This observation should help guide the search for more effective therapy against a specific subset of lung cancers.
    MeSH term(s) Adenocarcinoma/drug therapy ; Adenocarcinoma/genetics ; Antineoplastic Agents/pharmacology ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/genetics ; DNA Mutational Analysis ; Disease Progression ; Drug Resistance, Neoplasm/genetics ; ErbB Receptors/genetics ; Erlotinib Hydrochloride ; Exons ; Female ; Gefitinib ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Middle Aged ; Point Mutation ; Quinazolines/pharmacology ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured
    Chemical Substances Antineoplastic Agents ; Quinazolines ; Erlotinib Hydrochloride (DA87705X9K) ; ErbB Receptors (EC 2.7.10.1) ; Gefitinib (S65743JHBS)
    Language English
    Publishing date 2005-02-22
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2185925-5
    ISSN 1549-1676 ; 1549-1277
    ISSN (online) 1549-1676
    ISSN 1549-1277
    DOI 10.1371/journal.pmed.0020073
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.

    Regales, Lucia / Gong, Yixuan / Shen, Ronglai / de Stanchina, Elisa / Vivanco, Igor / Goel, Aviva / Koutcher, Jason A / Spassova, Maria / Ouerfelli, Ouathek / Mellinghoff, Ingo K / Zakowski, Maureen F / Politi, Katerina A / Pao, William

    The Journal of clinical investigation

    2009  Volume 119, Issue 10, Page(s) 3000–3010

    Abstract: EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas ... ...

    Abstract EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.
    MeSH term(s) Afatinib ; Amphiregulin ; Animals ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents/therapeutic use ; Cetuximab ; Disease Models, Animal ; Drug Resistance, Neoplasm/genetics ; EGF Family of Proteins ; Epidermal Growth Factor/genetics ; Epidermal Growth Factor/metabolism ; Epiregulin ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Erlotinib Hydrochloride ; Gene Expression Profiling ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Humans ; Intercellular Signaling Peptides and Proteins/genetics ; Intercellular Signaling Peptides and Proteins/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/pathology ; Male ; Mice ; Mice, Nude ; Mice, Transgenic ; Mutation ; Neoplasm Transplantation ; Paclitaxel/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Quinazolines/metabolism ; Quinazolines/therapeutic use ; Transplantation, Heterologous ; Tumor Cells, Cultured
    Chemical Substances AREG protein, human ; Amphiregulin ; Antibodies, Monoclonal ; Antibodies, Monoclonal, Humanized ; Antineoplastic Agents ; Areg protein, mouse ; EGF Family of Proteins ; EREG protein, human ; Epiregulin ; Ereg protein, mouse ; Glycoproteins ; Intercellular Signaling Peptides and Proteins ; Protein Kinase Inhibitors ; Quinazolines ; Afatinib (41UD74L59M) ; Epidermal Growth Factor (62229-50-9) ; Erlotinib Hydrochloride (DA87705X9K) ; ErbB Receptors (EC 2.7.10.1) ; Paclitaxel (P88XT4IS4D) ; Cetuximab (PQX0D8J21J)
    Language English
    Publishing date 2009-09-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI38746
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: BAC consensus conference, November 4-6, 2004: epidemiology, pathogenesis, and preclinical models.

    Christiani, David C / Pao, William / DeMartini, James C / Linnoila, R Ilona / Malkinson, Alvin M / Onn, Amir / Politi, Katerina A / Sharp, Michael / Wong, Kwok-Kin / Kim, Kwok

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

    2006  Volume 1, Issue 9 Suppl, Page(s) S2–7

    Abstract: Introduction: Human bronchioloalveolar carcinoma (BAC) is a disease with an evolving definition. "Pure" BAC, characterized by a bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion, represents only 2 to 6% of non- ... ...

    Abstract Introduction: Human bronchioloalveolar carcinoma (BAC) is a disease with an evolving definition. "Pure" BAC, characterized by a bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion, represents only 2 to 6% of non-small cell lung cancer (NSCLC) cases, but up to 20% of NSCLC cases may contain elements of BAC. This imprecise definition makes it difficult to perform epidemiologic analyses or to generate accurate animal models. However, because BAC appears to behave clinically differently from adenocarcinoma, a better understanding of this disease entity is imperative.
    Methods/results: At the BAC Consensus Conference in 2004, our committee discussed issues relevant to BAC epidemiology, pathogenesis, and preclinical models.
    Conclusions: Elucidation of molecular events involved in BAC tumorigenesis will allow for more precise epidemiologic studies and improved animal models, which will enable development of more effective treatments against the disease.
    MeSH term(s) Adenocarcinoma/epidemiology ; Adenocarcinoma/pathology ; Adenocarcinoma/physiopathology ; Adenocarcinoma, Bronchiolo-Alveolar/epidemiology ; Adenocarcinoma, Bronchiolo-Alveolar/pathology ; Adenocarcinoma, Bronchiolo-Alveolar/physiopathology ; Animals ; Biopsy, Needle ; Diagnosis, Differential ; Disease Models, Animal ; Female ; Humans ; Immunohistochemistry ; Lung Neoplasms/epidemiology ; Lung Neoplasms/pathology ; Lung Neoplasms/physiopathology ; Male ; Mice ; Mice, Nude ; Mice, Transgenic ; Neoplasm Staging ; Prevalence ; Prognosis ; Risk Assessment ; Sheep
    Language English
    Publishing date 2006-11
    Publishing country United States
    Document type Consensus Development Conference ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2432037-7
    ISSN 1556-1380 ; 1556-0864
    ISSN (online) 1556-1380
    ISSN 1556-0864
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer

    Sos, Martin L / Fischer, Stefanie / Ullrich, Roland / Peifer, Martin / Heuckmann, Johannes M / Koker, Mirjam / Heynck, Stefanie / Stückrath, Isabel / Weiss, Jonathan / Fischer, Florian / Michel, Kathrin / Goel, Aviva / Regales, Lucia / Politi, Katerina A / Perera, Samanthi / Getlik, Matthäus / Heukamp, Lukas C / Ansén, Sascha / Zander, Thomas /
    Beroukhim, Rameen / Kashkar, Hamid / Shokat, Kevan M / Sellers, William R / Rauh, Daniel / Orr, Christine / Hoeflich, Klaus P / Friedman, Lori / Wong, Kwok-Kin / Pao, William / Thomas, Roman K

    Proceedings of the National Academy of Sciences of the United States of America. 2009 Oct. 27, v. 106, no. 43

    2009  

    Abstract: In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes ... ...

    Abstract In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce "downstream" dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
    Keywords apoptosis ; clinical trials ; drugs ; lung neoplasms ; mitogen-activated protein kinase ; models ; mutants ; mutation ; neoplasm cells ; oncogene proteins ; patients ; phosphatidylinositol 3-kinase ; proto-oncogenes ; receptor protein-tyrosine kinase ; shrinkage ; signal transduction
    Language English
    Dates of publication 2009-1027
    Size p. 18351-18356.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0907325106
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.

    Sos, Martin L / Fischer, Stefanie / Ullrich, Roland / Peifer, Martin / Heuckmann, Johannes M / Koker, Mirjam / Heynck, Stefanie / Stückrath, Isabel / Weiss, Jonathan / Fischer, Florian / Michel, Kathrin / Goel, Aviva / Regales, Lucia / Politi, Katerina A / Perera, Samanthi / Getlik, Matthäus / Heukamp, Lukas C / Ansén, Sascha / Zander, Thomas /
    Beroukhim, Rameen / Kashkar, Hamid / Shokat, Kevan M / Sellers, William R / Rauh, Daniel / Orr, Christine / Hoeflich, Klaus P / Friedman, Lori / Wong, Kwok-Kin / Pao, William / Thomas, Roman K

    Proceedings of the National Academy of Sciences of the United States of America

    2009  Volume 106, Issue 43, Page(s) 18351–18356

    Abstract: In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes ... ...

    Abstract In cancer, genetically activated proto-oncogenes often induce "upstream" dependency on the activity of the mutant oncoprotein. Therapeutic inhibition of these activated oncoproteins can induce massive apoptosis of tumor cells, leading to sometimes dramatic tumor regressions in patients. The PI3K and MAPK signaling pathways are central regulators of oncogenic transformation and tumor maintenance. We hypothesized that upstream dependency engages either one of these pathways preferentially to induce "downstream" dependency. Therefore, we analyzed whether downstream pathway dependency segregates by genetic aberrations upstream in lung cancer cell lines. Here, we show by systematically linking drug response to genomic aberrations in non-small-cell lung cancer, as well as in cell lines of other tumor types and in a series of in vivo cancer models, that tumors with genetically activated receptor tyrosine kinases depend on PI3K signaling, whereas tumors with mutations in the RAS/RAF axis depend on MAPK signaling. However, efficacy of downstream pathway inhibition was limited by release of negative feedback loops on the reciprocal pathway. By contrast, combined blockade of both pathways was able to overcome the reciprocal pathway activation induced by inhibitor-mediated release of negative feedback loops and resulted in a significant increase in apoptosis and tumor shrinkage. Thus, by using a systematic chemo-genomics approach, we identify genetic lesions connected to PI3K and MAPK pathway activation and provide a rationale for combined inhibition of both pathways. Our findings may have implications for patient stratification in clinical trials.
    MeSH term(s) Apoptosis/drug effects ; Cell Line, Tumor ; Genotype ; Humans ; MAP Kinase Signaling System/drug effects ; Neoplasms/drug therapy ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/pathology ; Phosphatidylinositol 3-Kinases/genetics ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors/pharmacology
    Chemical Substances Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors
    Language English
    Publishing date 2009-10-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0907325106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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