Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains
Therapeutics that target ERBB2, such as lapatinib, often provide initial clinical benefit, but resistance frequently develops. Adaptive responses leading to lapatinib resistance involve reprogramming of the kinome through reactivation of ERBB2/ERBB3 signaling and transcriptional upregulation and act...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2015-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471500306X |
| _version_ | 1818020950451421184 |
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| author | Timothy J. Stuhlmiller Samantha M. Miller Jon S. Zawistowski Kazuhiro Nakamura Adriana S. Beltran James S. Duncan Steven P. Angus Kyla A.L. Collins Deborah A. Granger Rachel A. Reuther Lee M. Graves Shawn M. Gomez Pei-Fen Kuan Joel S. Parker Xin Chen Noah Sciaky Lisa A. Carey H. Shelton Earp Jian Jin Gary L. Johnson |
| author_facet | Timothy J. Stuhlmiller Samantha M. Miller Jon S. Zawistowski Kazuhiro Nakamura Adriana S. Beltran James S. Duncan Steven P. Angus Kyla A.L. Collins Deborah A. Granger Rachel A. Reuther Lee M. Graves Shawn M. Gomez Pei-Fen Kuan Joel S. Parker Xin Chen Noah Sciaky Lisa A. Carey H. Shelton Earp Jian Jin Gary L. Johnson |
| author_sort | Timothy J. Stuhlmiller |
| collection | DOAJ |
| description | Therapeutics that target ERBB2, such as lapatinib, often provide initial clinical benefit, but resistance frequently develops. Adaptive responses leading to lapatinib resistance involve reprogramming of the kinome through reactivation of ERBB2/ERBB3 signaling and transcriptional upregulation and activation of multiple tyrosine kinases. The heterogeneity of induced kinases prevents their targeting by a single kinase inhibitor, underscoring the challenge of predicting effective kinase inhibitor combination therapies. We hypothesized that, to make the tumor response to single kinase inhibitors durable, the adaptive kinome response itself must be inhibited. Genetic and chemical inhibition of BET bromodomain chromatin readers suppresses transcription of many lapatinib-induced kinases involved in resistance, including ERBB3, IGF1R, DDR1, MET, and FGFRs, preventing downstream SRC/FAK signaling and AKT reactivation. Combining inhibitors of kinases and chromatin readers prevents kinome adaptation by blocking transcription, generating a durable response to lapatinib, and overcoming the dilemma of heterogeneity in the adaptive response. |
| first_indexed | 2024-04-14T08:11:21Z |
| format | Article |
| id | doaj.art-ed7a28c1915c491791b6cd80ddc9e842 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-14T08:11:21Z |
| publishDate | 2015-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ed7a28c1915c491791b6cd80ddc9e8422022-12-22T02:04:32ZengElsevierCell Reports2211-12472015-04-0111339040410.1016/j.celrep.2015.03.037Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family BromodomainsTimothy J. Stuhlmiller0Samantha M. Miller1Jon S. Zawistowski2Kazuhiro Nakamura3Adriana S. Beltran4James S. Duncan5Steven P. Angus6Kyla A.L. Collins7Deborah A. Granger8Rachel A. Reuther9Lee M. Graves10Shawn M. Gomez11Pei-Fen Kuan12Joel S. Parker13Xin Chen14Noah Sciaky15Lisa A. Carey16H. Shelton Earp17Jian Jin18Gary L. Johnson19Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USAJoint Department of Biomedical Engineering at UNC-Chapel Hill and NC State University, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USAJoint Department of Biomedical Engineering at UNC-Chapel Hill and NC State University, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Biostatistics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USAEshelman School of Pharmacy, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USADepartment of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USATherapeutics that target ERBB2, such as lapatinib, often provide initial clinical benefit, but resistance frequently develops. Adaptive responses leading to lapatinib resistance involve reprogramming of the kinome through reactivation of ERBB2/ERBB3 signaling and transcriptional upregulation and activation of multiple tyrosine kinases. The heterogeneity of induced kinases prevents their targeting by a single kinase inhibitor, underscoring the challenge of predicting effective kinase inhibitor combination therapies. We hypothesized that, to make the tumor response to single kinase inhibitors durable, the adaptive kinome response itself must be inhibited. Genetic and chemical inhibition of BET bromodomain chromatin readers suppresses transcription of many lapatinib-induced kinases involved in resistance, including ERBB3, IGF1R, DDR1, MET, and FGFRs, preventing downstream SRC/FAK signaling and AKT reactivation. Combining inhibitors of kinases and chromatin readers prevents kinome adaptation by blocking transcription, generating a durable response to lapatinib, and overcoming the dilemma of heterogeneity in the adaptive response.http://www.sciencedirect.com/science/article/pii/S221112471500306X |
| spellingShingle | Timothy J. Stuhlmiller Samantha M. Miller Jon S. Zawistowski Kazuhiro Nakamura Adriana S. Beltran James S. Duncan Steven P. Angus Kyla A.L. Collins Deborah A. Granger Rachel A. Reuther Lee M. Graves Shawn M. Gomez Pei-Fen Kuan Joel S. Parker Xin Chen Noah Sciaky Lisa A. Carey H. Shelton Earp Jian Jin Gary L. Johnson Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains Cell Reports |
| title | Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains |
| title_full | Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains |
| title_fullStr | Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains |
| title_full_unstemmed | Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains |
| title_short | Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains |
| title_sort | inhibition of lapatinib induced kinome reprogramming in erbb2 positive breast cancer by targeting bet family bromodomains |
| url | http://www.sciencedirect.com/science/article/pii/S221112471500306X |
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