Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction
The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but t...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2019-08-01
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| Series: | Platelets |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/09537104.2018.1514107 |
| _version_ | 1827816940305907712 |
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| author | Amanda J. Unsworth Alexander P. Bye Neline Kriek Tanya Sage Ashley A. Osborne Dillon Donaghy Jonathan M. Gibbins |
| author_facet | Amanda J. Unsworth Alexander P. Bye Neline Kriek Tanya Sage Ashley A. Osborne Dillon Donaghy Jonathan M. Gibbins |
| author_sort | Amanda J. Unsworth |
| collection | DOAJ |
| description | The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy. |
| first_indexed | 2024-03-12T00:27:21Z |
| format | Article |
| id | doaj.art-bc64c667e4ca4e5497016e2359c4b0d5 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:27:21Z |
| publishDate | 2019-08-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-bc64c667e4ca4e5497016e2359c4b0d52023-09-15T10:32:00ZengTaylor & Francis GroupPlatelets0953-71041369-16352019-08-0130676277210.1080/09537104.2018.15141071514107Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunctionAmanda J. Unsworth0Alexander P. Bye1Neline Kriek2Tanya Sage3Ashley A. Osborne4Dillon Donaghy5Jonathan M. Gibbins6University of Reading, School of Biological SciencesUniversity of Reading, School of Biological SciencesUniversity of Reading, School of Biological SciencesUniversity of Reading, School of Biological SciencesUniversity of Reading, School of Biological SciencesColorado State UniversityUniversity of Reading, School of Biological SciencesThe MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy.http://dx.doi.org/10.1080/09537104.2018.1514107erkmekplateletsthrombosis |
| spellingShingle | Amanda J. Unsworth Alexander P. Bye Neline Kriek Tanya Sage Ashley A. Osborne Dillon Donaghy Jonathan M. Gibbins Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction Platelets erk mek platelets thrombosis |
| title | Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction |
| title_full | Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction |
| title_fullStr | Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction |
| title_full_unstemmed | Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction |
| title_short | Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction |
| title_sort | cobimetinib and trametinib inhibit platelet mek but do not cause platelet dysfunction |
| topic | erk mek platelets thrombosis |
| url | http://dx.doi.org/10.1080/09537104.2018.1514107 |
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