A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040
PD184352/CI-1040 is a potent and selective MEK1/2 inhibitor that represents the first MEK-targeted agent to enter clinical trials. Here, we report the development and molecular characterization of CI-1040 resistance in the murine colon 26 (C26) carcinoma cell line. The growth rate of the resistant l...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2005-04-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S147655860580065X |
| _version_ | 1818364298141892608 |
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| author | Yuli Wangab Keri Van Becelaere Ping Jiang Sally Przybranowski Charles Omer Judith Sebolt-Leopold |
| author_facet | Yuli Wangab Keri Van Becelaere Ping Jiang Sally Przybranowski Charles Omer Judith Sebolt-Leopold |
| author_sort | Yuli Wangab |
| collection | DOAJ |
| description | PD184352/CI-1040 is a potent and selective MEK1/2 inhibitor that represents the first MEK-targeted agent to enter clinical trials. Here, we report the development and molecular characterization of CI-1040 resistance in the murine colon 26 (C26) carcinoma cell line. The growth rate of the resistant line (C26/CI-1040r) in the presence of 2 μM CI-1040 is comparable to that of parental C26 cells in the absence of CI-1040. C26/CI-1040r cells are approximately 100-fold more resistant than the parental line to CI-1040 inhibition in soft agar and are less sensitive to the induction of apoptosis that normally occurs in response to CI-1040 treatment. K-ras expression is significantly elevated in C26/CI-1040r cells. We confirmed a causative role for K-ras in conferring resistance to CI-1040 by transfecting K-ras into parental C26 cells, whereupon an elevation in the levels of phosphorylated ERK1/2 was observed in addition to resistance to CI-1040. Furthermore, an in vivo-derived MEK inhibitor-resistant line also shows increased K-ras expression. Our data suggest that increasing activated K-ras expression represents one potential mechanism by which tumor cells that initially are responsive to blockade of the MAP kinase pathway can overcome their sensitivity to MEK inhibition. |
| first_indexed | 2024-12-13T22:02:08Z |
| format | Article |
| id | doaj.art-b2b6a25a37cf43719d13564e012ba8a6 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-13T22:02:08Z |
| publishDate | 2005-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-b2b6a25a37cf43719d13564e012ba8a62022-12-21T23:29:58ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022005-04-017433634710.1593/neo.04532A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040Yuli WangabKeri Van BecelaerePing JiangSally PrzybranowskiCharles OmerJudith Sebolt-LeopoldPD184352/CI-1040 is a potent and selective MEK1/2 inhibitor that represents the first MEK-targeted agent to enter clinical trials. Here, we report the development and molecular characterization of CI-1040 resistance in the murine colon 26 (C26) carcinoma cell line. The growth rate of the resistant line (C26/CI-1040r) in the presence of 2 μM CI-1040 is comparable to that of parental C26 cells in the absence of CI-1040. C26/CI-1040r cells are approximately 100-fold more resistant than the parental line to CI-1040 inhibition in soft agar and are less sensitive to the induction of apoptosis that normally occurs in response to CI-1040 treatment. K-ras expression is significantly elevated in C26/CI-1040r cells. We confirmed a causative role for K-ras in conferring resistance to CI-1040 by transfecting K-ras into parental C26 cells, whereupon an elevation in the levels of phosphorylated ERK1/2 was observed in addition to resistance to CI-1040. Furthermore, an in vivo-derived MEK inhibitor-resistant line also shows increased K-ras expression. Our data suggest that increasing activated K-ras expression represents one potential mechanism by which tumor cells that initially are responsive to blockade of the MAP kinase pathway can overcome their sensitivity to MEK inhibition.http://www.sciencedirect.com/science/article/pii/S147655860580065XMEKERKRasCI-1040C26 |
| spellingShingle | Yuli Wangab Keri Van Becelaere Ping Jiang Sally Przybranowski Charles Omer Judith Sebolt-Leopold A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040 Neoplasia: An International Journal for Oncology Research MEK ERK Ras CI-1040 C26 |
| title | A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040 |
| title_full | A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040 |
| title_fullStr | A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040 |
| title_full_unstemmed | A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040 |
| title_short | A Role for K-ras in Conferring Resistance to the MEK Inhibitor, CI-1040 |
| title_sort | role for k ras in conferring resistance to the mek inhibitor ci 1040 |
| topic | MEK ERK Ras CI-1040 C26 |
| url | http://www.sciencedirect.com/science/article/pii/S147655860580065X |
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