Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance
Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cell...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-11-01
|
| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223012787 |
| _version_ | 1797660593097801728 |
|---|---|
| author | Angelina Pranteda Valentina Piastra Martina Serra Roberta Bernardini Federica Lo Sardo Silvia Carpano Maria Grazia Diodoro Armando Bartolazzi Michele Milella Giovanni Blandino Gianluca Bossi |
| author_facet | Angelina Pranteda Valentina Piastra Martina Serra Roberta Bernardini Federica Lo Sardo Silvia Carpano Maria Grazia Diodoro Armando Bartolazzi Michele Milella Giovanni Blandino Gianluca Bossi |
| author_sort | Angelina Pranteda |
| collection | DOAJ |
| description | Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of Mitogen-Activated Protein Kinase Kinase 3 (MKK3), a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene expression profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the roles of MKK3 in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAFV600E CRC lines and derived dabrafenib-resistant (DABR) sublines. Dabrafenib treatments reduce MKK3 activation by inducing autophagy in parental but not DABR cells. The MKK3 knockdown induces cell death in DABR cells, whereas ectopic MKK3 expression reduces dabrafenib sensitivity in parental cells. Mechanistically, activated MKK3 interacts and co-localizes with c-Myc oncoprotein (MYC), sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding light on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAFV600E CRC. |
| first_indexed | 2024-03-11T18:32:09Z |
| format | Article |
| id | doaj.art-9d7b8cc690a34230a359df41b031e9c8 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-11T18:32:09Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-9d7b8cc690a34230a359df41b031e9c82023-10-13T11:02:46ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-11-01167115480Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistanceAngelina Pranteda0Valentina Piastra1Martina Serra2Roberta Bernardini3Federica Lo Sardo4Silvia Carpano5Maria Grazia Diodoro6Armando Bartolazzi7Michele Milella8Giovanni Blandino9Gianluca Bossi10Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Department of Science, University Roma TRE, Viale G. Marconi, 446 I, 00146 Rome, ItalyTranslational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Department of Science, University Roma TRE, Viale G. Marconi, 446 I, 00146 Rome, ItalyInterdepartmental Centre for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome ''Tor Vergata, Via Montpellier, 1, 00133 Rome, ItalyInterdepartmental Centre for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome ''Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy; Center for Research and Services ''Preclinical Experimentation and Animal Welfare'' (SPBA), University of Rome ''La Sapienza'', Piazzale Aldo Moro, 5, 00185 Rome, ItalyTranslational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, ItalySecond Division of Medical Oncology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, ItalyDepartment of Pathology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, ItalyPathology Research Laboratory, Sant'Andrea University Hospital, Via di Grottarossa, 1035, 00189 Rome, ItalyUOC of Oncology, Verona University and Hospital Trust (Azienda Ospedaliera Universitaria Integrata-AOUI-Verona), Piazzale Aristide Stefani, 1, 37126 Verona, ItalyTranslational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, ItalyTranslational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Corresponding author.Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of Mitogen-Activated Protein Kinase Kinase 3 (MKK3), a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene expression profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the roles of MKK3 in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAFV600E CRC lines and derived dabrafenib-resistant (DABR) sublines. Dabrafenib treatments reduce MKK3 activation by inducing autophagy in parental but not DABR cells. The MKK3 knockdown induces cell death in DABR cells, whereas ectopic MKK3 expression reduces dabrafenib sensitivity in parental cells. Mechanistically, activated MKK3 interacts and co-localizes with c-Myc oncoprotein (MYC), sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding light on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAFV600E CRC.http://www.sciencedirect.com/science/article/pii/S0753332223012787Colorectal Cancer (CRC)MKK3 / p38MAPKMYCBRAF target therapy |
| spellingShingle | Angelina Pranteda Valentina Piastra Martina Serra Roberta Bernardini Federica Lo Sardo Silvia Carpano Maria Grazia Diodoro Armando Bartolazzi Michele Milella Giovanni Blandino Gianluca Bossi Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance Biomedicine & Pharmacotherapy Colorectal Cancer (CRC) MKK3 / p38MAPK MYC BRAF target therapy |
| title | Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance |
| title_full | Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance |
| title_fullStr | Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance |
| title_full_unstemmed | Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance |
| title_short | Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance |
| title_sort | activated mkk3 myc crosstalk impairs dabrafenib response in brafv600e colorectal cancer leading to resistance |
| topic | Colorectal Cancer (CRC) MKK3 / p38MAPK MYC BRAF target therapy |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223012787 |
| work_keys_str_mv | AT angelinapranteda activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT valentinapiastra activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT martinaserra activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT robertabernardini activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT federicalosardo activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT silviacarpano activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT mariagraziadiodoro activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT armandobartolazzi activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT michelemilella activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT giovanniblandino activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance AT gianlucabossi activatedmkk3myccrosstalkimpairsdabrafenibresponseinbrafv600ecolorectalcancerleadingtoresistance |