Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1.
Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive "active-site" mTOR i...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3931643?pdf=render |
| _version_ | 1818267007234080768 |
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| author | Sharmila Mallya Briana A Fitch J Scott Lee Lomon So Matthew R Janes David A Fruman |
| author_facet | Sharmila Mallya Briana A Fitch J Scott Lee Lomon So Matthew R Janes David A Fruman |
| author_sort | Sharmila Mallya |
| collection | DOAJ |
| description | Inhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive "active-site" mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors. |
| first_indexed | 2024-12-12T20:15:45Z |
| format | Article |
| id | doaj.art-0fed3c60e9c14cf0996c32472f87197d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T20:15:45Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-0fed3c60e9c14cf0996c32472f87197d2022-12-22T00:13:23ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0192e8886510.1371/journal.pone.0088865Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1.Sharmila MallyaBriana A FitchJ Scott LeeLomon SoMatthew R JanesDavid A FrumanInhibitors of the mechanistic target of rapamycin (mTOR) hold promise for treatment of hematological malignancies. Analogs of the allosteric mTOR inhibitor rapamycin are approved for mantle cell lymphoma but have limited efficacy in other blood cancers. ATP-competitive "active-site" mTOR inhibitors produce more complete mTOR inhibition and are more effective than rapamycin in preclinical models of leukemia, lymphoma and multiple myeloma. In parallel to clinical trials of active-site mTOR inhibitors, it will be important to identify resistance mechanisms that might limit drug efficacy in certain patients. From a panel of diffuse large B-cell lymphoma cell lines, we found that the VAL cell line is particularly resistant to apoptosis in the presence of active-site mTOR inhibitors. Mechanistic investigation showed that VAL does not express eukaryotic initiation factor 4E-binding protein-1 (4EBP1), a key negative regulator of translation controlled by mTOR. Although VAL cells express the related protein 4EBP2, mTOR inhibitor treatment fails to displace eukaryotic initiation factor 4G from the mRNA cap-binding complex. Knockdown of eukaryotic initiation factor 4E, or re-expression of 4EBP1, sensitizes cells to apoptosis when treated with active-site mTOR inhibitors. These findings provide a naturally occurring example of 4EBP deficiency driving lymphoma cell resistance to active-site mTOR inhibitors.http://europepmc.org/articles/PMC3931643?pdf=render |
| spellingShingle | Sharmila Mallya Briana A Fitch J Scott Lee Lomon So Matthew R Janes David A Fruman Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. PLoS ONE |
| title | Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. |
| title_full | Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. |
| title_fullStr | Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. |
| title_full_unstemmed | Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. |
| title_short | Resistance to mTOR kinase inhibitors in lymphoma cells lacking 4EBP1. |
| title_sort | resistance to mtor kinase inhibitors in lymphoma cells lacking 4ebp1 |
| url | http://europepmc.org/articles/PMC3931643?pdf=render |
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