Genomes and Genes
Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma
Principal Investigator: Matthew L Meyerson
Abstract: DESCRIPTION (provided by applicant): This Program aims to develop three protein kinases, inhibitor-resistant EGFR, TBK1, and DDR2, as therapeutic targets in non-small cell lung cancer (NSCLC). These targets were chosen because patients are treated with mutation-selective therapy but typically develop resistance (EGFR), because the mutation is common and there is no effective targeted agent but we have an excellent candidate downstream target (TBK1 for mutant KRAS), or because there is a new genomic alteration providing an opportunity for a lung cancer histology, squamous cell carcinoma, for which there is no validated target (DDR2). Our program integrates molecular and cellular pharmacology, chemistry, structural biology and mouse modeling with the overarching aim of developing specific kinase inhibitors that are active in cell-based and genetically engineered mouse models, through the following specific aims. -Overall aim 1. Develop potent and where possible mutant-selective inhibitors of inhibitor-resistant EGFR, TBK1, and DDR2 using medicinal chemistry and structure-based drug design. Core A (Chemistry) has developed promising lead compounds to inhibit pyrimidine inhibitor-resistant EGFR (Project 1), TBK1 (Project 2), and DDR2 (Project 3). Each project will collaborate with Cores A (Chemistry) and B (Structure) to optimize compounds based on cellular screens and on structural analysis of purified kinases. -Overall aim 2. Characterize kinase inhibitors and their targets pharmacologically using cellular and animal therapeutic models of lung cancer. Investigators from each Project will work with Core C (Animal) to continue generating and studying genetically engineered mouse models of lung cancer relevant to each kinase. -Overall aim 3. Employ rational design and cell-based approaches to identify inhibitor resistance mutations and to use this information in kinase inhibitor design and optimization. Our insight into resistance to EGFR inhibitors will be used to design new inhibitors that overcome drug resistance mutations for all three targets.
Funding Period: 2012-05-11 - 2017-04-30
more information: NIH RePORT
- LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanomaWenjin Liu
Department of Genetics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599 7295, USA
Cancer Cell 21:751-64. 2012..These results suggest that LKB1 inactivation in the context of RAS activation facilitates metastasis by inducing an SFK-dependent expansion of a prometastatic, CD24(+) tumor subpopulation...
- Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 lossEllen M Beauchamp
Corresponding Author Peter S Hammerman, Dana Farber Cancer Institute, 450 Brookline Avenue, Dana 810A, Boston, MA 02215
Mol Cancer Ther 13:475-82. 2014..These data may help to anticipate mechanisms of resistance that may be identified in upcoming clinical trials of anti-DDR2 therapy in lung cancer and suggest strategies to overcome resistance...
- Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistanceZhao Chen
Authors Affiliations Department of Medicine, Harvard Medical School Departments of Medical Oncology and Imaging, Lowe Center for Thoracic Oncology, Department of Pediatrics, Columbia University Medical Center, New York, New York, Ludwig Center at Dana Farber Harvard Cancer Center, Early Drug Development Center, Dana Farber Cancer Institute Department of Medical Oncology, Massachusetts General Hospital Cancer Center Department of Radiology, Brigham and Women s Hospital, Boston, Massachusetts and Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, North Carolina
Clin Cancer Res 20:1204-11. 2014..To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion...
- Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancerHiroyuki Yasuda
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Sci Transl Med 5:216ra177. 2013..Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs. ..
- Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuitZehua Zhu
Departments of 1Medical Oncology and 2Cancer Biology, Dana Farber Cancer Institute 3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston 4Broad Institute of Harvard and MIT, Cambridge 5MGH Cancer Center, 6Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Charlestown, Massachusetts and 7Department of Surgery, Division of Biology and Biomedical Sciences, Washington University, St Louis, Missouri
Cancer Discov 4:452-65. 2014....
- Oncogenic RIT1 mutations in lung adenocarcinomaA H Berger
1 Cancer Program, The Broad Institute of Harvard and M I T, 7 Cambridge Center, Cambridge, MA, USA 2 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA
Oncogene 33:4418-23. 2014..These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors. ..
- Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expressionChunxiao Xu
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, MA 02215, USA
Cancer Cell 25:590-604. 2014..TPCs in the LP model and NGFR(+) cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs. ..
- Loss of p53 attenuates the contribution of IL-6 deletion on suppressed tumor progression and extended survival in Kras-driven murine lung cancerXiaohong Tan
State Key Laboratory of Proteomics, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, China Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS ONE 8:e80885. 2013..However, these effects can be attenuated by p53 deletion...
- The quest to overcome resistance to EGFR-targeted therapies in cancerCurtis R Chong
1 Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA 2 Department of Medicine, Brigham and Women s Hospital, Boston, Massachusetts, USA
Nat Med 19:1389-400. 2013..We present a comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers and discuss therapeutic strategies that are designed to circumvent resistance. ..
- Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumorsEsra A Akbay
Departments of 1Medicine and 2Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute 3Harvard Medical School 4Ludwig Institute for Cancer Research 5Department of Neurosurgery, Massachusetts General Hospital 6Belfer Institute for Applied Cancer Science 7Department of Pathology, Brigham and Women s Hospital, Boston 8Broad Institute, Cambridge, Massachusetts 9UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina and 10Department of Molecular Pharmacology and Therapeutics, Oncology Institute, Loyola University, Chicago, Illinois 11Department of Physiology, University of Valencia, Valencia, Spain
Cancer Discov 3:1355-63. 2013..These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition...
- Reactivation of ERK signaling causes resistance to EGFR kinase inhibitorsDalia Ercan
Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
Cancer Discov 2:934-47. 2012..Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials...
- Structure and ubiquitination-dependent activation of TANK-binding kinase 1Daqi Tu
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA
Cell Rep 3:747-58. 2013..The structure of TBK1 will facilitate studies of the atypical IKKs in normal and disease physiology and further the development of more specific inhibitors that may be useful as anticancer or anti-inflammatory agents...
- Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancerYan Liu
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Cancer Discov 3:870-9. 2013..Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors. ..
- Discovery of a potent and selective DDR1 receptor tyrosine kinase inhibitorHyung Gu Kim
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States
ACS Chem Biol 8:2145-50. 2013..DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction. ..
- New cast for a new era: preclinical cancer drug development revisitedGrit S Herter-Sprie
Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
J Clin Invest 123:3639-45. 2013..Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes. ..
- Mechanism for activation of mutated epidermal growth factor receptors in lung cancerMonica Red Brewer
Division of Hematology Oncology, Department of Medicine, Vanderbilt University, Nashville, TN 37232
Proc Natl Acad Sci U S A 110:E3595-604. 2013..Collectively, these findings define a previously unrecognized mode of mutant-specific intermolecular regulation for ErbB receptors, knowledge of which could potentially be exploited for therapeutic benefit. ..
- Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancerTakeshi Shimamura
Authors Affiliations Department of Molecular Pharmacology and Therapeutics, Oncology Research Institute, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois Departments of Medical Oncology and Radiation Oncology Belfer Institute for Applied Cancer Science Ludwig Center at Dana Farber Harvard Cancer Center Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute Department of Medicine, Brigham and Women s Hospital Department of Medicine, Harvard Medical School, Boston, Massachusetts Departament de Fisiologia, Facultat de Farmacia, Universitat de Valencia, Valencia, Spain and Department of Pediatrics, Columbia University Medical Center, New York, New York
Clin Cancer Res 19:6183-92. 2013....
- Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerizationJeonghee Cho
Authors Affiliations Departments of Medical Oncology and Cancer Biology Center for Cancer Genome Discovery, Lowe Center for Thoracic Oncology, and Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute Departments of Medicine, Brigham and Women s Hospital Departments of Biological Chemistry and Molecular Pharmacology and Pathology, Harvard Medical School, Boston, Massachusetts Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea and The Broad Institute of Harvard and MIT, Cambridge, Massachusetts
Cancer Res 73:6770-9. 2013..These data imply that different EGFR mutants show differential requirements for dimerization and that disruption of dimerization may be among the antitumor mechanisms of cetuximab...