ArticleCancer cell2015
A functional landscape of resistance to ALK inhibition in lung cancer.
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Article in Cancer cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers.
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110citing papers in PubMed
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Who cites it
110 citing papers in PubMed, 173 citations in OpenAlex.
- The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers.Clinical pharmacology in drug development · 2019Trial
- Pyridine-containing antitumor agents: structure-oriented medicinal chemistry, structure-activity relationships, and ADMET liabilities.Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Review
- Research on the correlation and potential mechanism of PKCδ expression with efficacy and prognosis in diffuse large B-cell lymphoma.Frontiers in oncology · 2026Article
- Effects of nanoflubendazole and purinergic signaling modulation in overcoming neuroblastoma chemoresistance.Purinergic signalling · 2025Article
- High-intensity light disrupts intracellular organelle dynamics via microtubule depolymerization.Scientific reports · 2025Article
- Emerging importance of HER3 in tumorigenesis and cancer therapy.Nature reviews. Clinical oncology · 2025Review
- Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer.International journal of general medicine · 2025Review
- Fuel for thought: targeting metabolism in lung cancer.Translational lung cancer research · 2024Review
- Prevalence of HER3 Expression in Pancreatic Cancer Patients Treated With Systemic Chemotherapy.Cancer medicine · 2024Article
- AXL and SHC1 confer crizotinib resistance in patient-derived xenograft model of ALK-driven lung cancer.iScience · 2024Article
- HER3 overexpression: a predictive marker for poor prognosis in advanced ALK-positive non-small cell lung cancer treated with ALK inhibitors.Translational lung cancer research · 2024Article
- MIG6 Mediates Adaptive and Acquired Resistance to ALK/ROS1 Fusion Kinase Inhibition through EGFR Bypass Signaling.Molecular cancer therapeutics · 2024Article
- Research progress on the role of bypass activation mechanisms in resistance to tyrosine kinase inhibitors in non-small cell lung cancer.Frontiers in oncology · 2024Review
- Role of human epidermal growth factor receptor 3 in treatment resistance of anaplastic lymphoma kinase translocated non-small cell lung cancer.Cancer biology & therapy · 2023Article
- Review
- Using evolutionary constraint to define novel candidate driver genes in medulloblastoma.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- PI3Kβ inhibition enhances ALK-inhibitor sensitivity in ALK-rearranged lung cancer.Molecular oncology · 2023Article
- ALK-positive lung cancer: a moving target.Nature cancer · 2023Review
- Review
- Silibinin Overcomes EMT-Driven Lung Cancer Resistance to New-Generation ALK Inhibitors.Cancers · 2022Article
50 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 3 institutions in 1 country.
Frederick H WilsonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Cory M JohannessenThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Federica PiccioniThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Pablo TamayoThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jong Wook KimDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Eliezer M Van AllenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Steven M CorselloDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Marzia CapellettiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Antonio CallesDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Mohit ButaneyDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Tanaz SharifniaDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Stacey B GabrielThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jill P MesirovThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
William C HahnDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jeffrey A EngelmanMassachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA.
Matthew MeyersonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
David E RootThe Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Pasi A JänneDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Levi A GarrawayDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: levi_garraway@dfci.harvard.edu.
Broad Institute · USHarvard University · USMassachusetts General Hospital · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MSignatures of Kinase Activation in Cancer (MIT consortium)U54CA112962 · NCI · DANA-FARBER CANCER INSTITUTE · PI GOLUB, TODD R. · 2004 to 2014
$24.2MStructureP01CA154303 · NCI · DANA-FARBER CANCER INST · PI MEYERSON, MATTHEW L. · 2012 to 2021
$17.8MPhysician Scientist Training in Cancer ResearchT32CA009172 · NCI · DANA-FARBER CANCER INSTITUTE · PI Jennifer R Brown, James A. DeCaprio · 1985 to 2026
$17.1MLarge scale gene expression analysis of cellular statesU54HG006093 · NHGRI · BROAD INSTITUTE, INC. · PI GOLUB, TODD R., SUBRAMANIAN, ARAVIND · 2010 to 2013
$9.1MThe Dana-Farber Cancer Institute Cancer Target Discovery and Development CenterU01CA176058 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2013 to 2021
$7.8MSupporting Integrative Genomic Analysis Users with GenePatternR01GM074024 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2005 to 2019
$6.6MKnowledge-based Gene Expression Analysis for Biomedical and Cancer ResearchR01CA121941 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI MESIROV, JILL P. · 2006 to 2016
$5.1MTargeting ALK through Degradation and Allosteric InhibitorsR01CA136851 · NCI · STANFORD UNIVERSITY · PI GRAY, NATHANAEL SCHIANDER, JANNE, PASI A · 2009 to 2023
$4.6MDefining Melanoma Therapeutic Avenues by Integrative Functional GenomicsDP2OD002750 · OD · DANA-FARBER CANCER INST · PI GARRAWAY, LEVI ALEXANDER · 2007 to 2007
$2.6MMolecular Signatures to Characterize the Oncogenic State of Individual TumorsR01CA154480 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI TAMAYO, PABLO · 2011 to 2015
$2.0MHigh-Throughput Tumor Genomic Profiling by Massively Parallel SequencingR33CA155554 · NCI · DANA-FARBER CANCER INST · PI GARRAWAY, LEVI A., MACCONAILL, LAURA E · 2011 to 2013
$717kNCCDPHP CDC HHS DP2 0D002750NCI NIH HHS NIH 5R33CA155554-03NCI NIH HHS NIH R01 CA136851NCI NIH HHS NIH R01 CA154480NCI NIH HHS P01 CA154303NCI NIH HHS R01 CA121941NCI NIH HHS R01 CA136851NCI NIH HHS R01 CA154480NCI NIH HHS R33 CA155554NCI NIH HHS T32 CA009172NCI NIH HHS U01 CA176058NCI NIH HHS U54 CA112962NHGRI NIH HHS #5U54HG003067-11NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG006093NIGMS NIH HHS GM074024NIGMS NIH HHS R01 GM074024
Abstract
We conducted a large-scale functional genetic study to characterize mechanisms of resistance to ALK inhibition in ALK-dependent lung cancer cells. We identify members of known resistance pathways and additional putative resistance drivers. Among the latter were members of the P2Y purinergic receptor family of G-protein-coupled receptors (P2Y1, P2Y2, and P2Y6). P2Y receptors mediated resistance in part through a protein-kinase-C (PKC)-dependent mechanism. Moreover, PKC activation alone was sufficient to confer resistance to ALK inhibitors, whereas combined ALK and PKC inhibition restored sensitivity. We observed enrichment of gene signatures associated with several resistance drivers (including P2Y receptors) in crizotinib-resistant ALK-rearranged lung tumors compared to treatment-naive controls, supporting a role for these identified mechanisms in clinical ALK inhibitor resistance.
Indexed as
Anaplastic Lymphoma KinaseCarcinoma, Non-Small-Cell LungCell Line, TumorCrizotinibDrug Resistance, NeoplasmErb-b2 Receptor Tyrosine KinasesErbB ReceptorsHumansLung NeoplasmsPyrazolesPyridinesReceptor Protein-Tyrosine KinasesReceptors, Purinergic P2YSignal TransductionALK protein, humanAnaplastic Lymphoma KinaseCrizotinibEGFR protein, humanERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesErbB ReceptorsPyrazolesPyridinesReceptor Protein-Tyrosine KinasesReceptors, Purinergic P2Y
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