RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1 -Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade

The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resi...

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Published inMolecular cancer therapeutics Vol. 17; no. 7; pp. 1526 - 1539
Main Authors Bockorny, Bruno, Rusan, Maria, Chen, Wankun, Liao, Rachel G, Li, Yvonne, Piccioni, Federica, Wang, Jun, Tan, Li, Thorner, Aaron R, Li, Tianxia, Zhang, Yanxi, Miao, Changhong, Ovesen, Therese, Shapiro, Geoffrey I, Kwiatkowski, David J, Gray, Nathanael S, Meyerson, Matthew, Hammerman, Peter S, Bass, Adam J
Format Journal Article
LanguageEnglish
Published United States American Association for Cancer Research Inc 01.07.2018
Subjects
Activation
Animals
Axl protein
Bladder
Cancer
Cholangiocarcinoma
Chronic exposure
Clinical trials
Cloning
Drug Resistance, Neoplasm - genetics
Extracellular signal-regulated kinase
Fibroblast growth factor receptor 1
Fibroblast growth factor receptors
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Genomes
Head & neck cancer
Humans
Inhibition
Inhibitors
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
MAP kinase
MAP Kinase Kinase Kinase 1 - antagonists & inhibitors
MAP Kinase Kinase Kinase 1 - genetics
Medical research
Mice
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - genetics
Mutation
Protein Kinase Inhibitors - pharmacology
Protein-tyrosine kinase receptors
Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 - genetics
Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 - genetics
Signal Transduction - drug effects
Squamous cell carcinoma
Therapeutic applications
Tyrosine
Xenograft Model Antitumor Assays
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Abstract The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a -dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS-MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. .
AbstractList The Fibroblast Growth Factor Receptor (FGFR) kinases are promising therapeutic targets in multiple cancer types including lung and head and neck squamous cell carcinoma, cholangiocarcinoma and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1 -dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRKs), the TAM family of tyrosine kinases ( TYRO3 , MERTK , AXL ) and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1 - and FGFR3 -dependent cellular models, and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, co-inhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant re-activation of RAS-MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR-dependencies, and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers.
The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a -dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS-MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. .
Abstract The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1-dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS–MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. Mol Cancer Ther; 17(7); 1526–39. ©2018 AACR.
The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and bladder cancer. Although several FGFR kinase inhibitors have entered clinical trials, single-agent clinical efficacy has been modest and resistance invariably occurs. We therefore conducted a genome-wide functional screen to characterize mechanisms of resistance to FGFR inhibition in a FGFR1-dependent lung cancer cellular model. Our screen identified known resistance drivers, such as MET, and additional novel resistance mediators including members of the neurotrophin receptor pathway (NTRK), the TAM family of tyrosine kinases (TYRO3, MERTK, AXL), and MAPK pathway, which were further validated in additional FGFR-dependent models. In an orthogonal approach, we generated a large panel of resistant clones by chronic exposure to FGFR inhibitors in FGFR1- and FGFR3-dependent cellular models and characterized gene expression profiles employing the L1000 platform. Notably, resistant clones had enrichment for NTRK and MAPK signaling pathways. Novel mediators of resistance to FGFR inhibition were found to compensate for FGFR loss in part through reactivation of MAPK pathway. Intriguingly, coinhibition of FGFR and specific receptor tyrosine kinases identified in our screen was not sufficient to suppress ERK activity or to prevent resistance to FGFR inhibition, suggesting a redundant reactivation of RAS–MAPK pathway. Dual blockade of FGFR and MEK, however, proved to be a more powerful approach in preventing resistance across diverse FGFR dependencies and may represent a therapeutic opportunity to achieve durable responses to FGFR inhibition in FGFR-dependent cancers. Mol Cancer Ther; 17(7); 1526–39. ©2018 AACR.
Author Chen, Wankun
Zhang, Yanxi
Tan, Li
Kwiatkowski, David J
Miao, Changhong
Li, Yvonne
Gray, Nathanael S
Bass, Adam J
Wang, Jun
Li, Tianxia
Ovesen, Therese
Piccioni, Federica
Thorner, Aaron R
Bockorny, Bruno
Liao, Rachel G
Meyerson, Matthew
Hammerman, Peter S
Rusan, Maria
Shapiro, Geoffrey I
AuthorAffiliation 12 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
5 Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
6 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
11 Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA
9 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai, 201210, China
3 Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
4 Department of Clinical Medicine, Aarhus University, Aarhus, 8000, Denmark
7 Genetic Perturbation Platform, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
2 Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
8 Department of Integrative Medicine and Neurobiology, Institute
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  organization: Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
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  organization: Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts
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Snippet The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma, cholangiocarcinoma, and...
Abstract The FGFR kinases are promising therapeutic targets in multiple cancer types, including lung and head and neck squamous cell carcinoma,...
The Fibroblast Growth Factor Receptor (FGFR) kinases are promising therapeutic targets in multiple cancer types including lung and head and neck squamous cell...
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SubjectTerms Activation
Animals
Axl protein
Bladder
Cancer
Cholangiocarcinoma
Chronic exposure
Clinical trials
Cloning
Drug Resistance, Neoplasm - genetics
Extracellular signal-regulated kinase
Fibroblast growth factor receptor 1
Fibroblast growth factor receptors
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Genomes
Head & neck cancer
Humans
Inhibition
Inhibitors
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
MAP kinase
MAP Kinase Kinase Kinase 1 - antagonists & inhibitors
MAP Kinase Kinase Kinase 1 - genetics
Medical research
Mice
Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases - genetics
Mutation
Protein Kinase Inhibitors - pharmacology
Protein-tyrosine kinase receptors
Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 - genetics
Receptor, Fibroblast Growth Factor, Type 3 - antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 3 - genetics
Signal Transduction - drug effects
Squamous cell carcinoma
Therapeutic applications
Tyrosine
Xenograft Model Antitumor Assays
Title RAS-MAPK Reactivation Facilitates Acquired Resistance in FGFR1 -Amplified Lung Cancer and Underlies a Rationale for Upfront FGFR-MEK Blockade
URI https://www.ncbi.nlm.nih.gov/pubmed/29654068
https://www.proquest.com/docview/2062692917
https://pubmed.ncbi.nlm.nih.gov/PMC6030474
Volume 17
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