Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I
<p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses <it>BCR</it> to <it>ABL</it> resulting in deregulated AB...
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2012-09-01
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| Series: | BMC Cancer |
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| Online Access: | http://www.biomedcentral.com/1471-2407/12/411 |
| _version_ | 1831558385969922048 |
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| author | Mian Afsar Metodieva Anna Badura Susanne Khateb Mamduh Ruimi Nili Najajreh Yousef Ottmann Oliver Mahajna Jamal Ruthardt Martin |
| author_facet | Mian Afsar Metodieva Anna Badura Susanne Khateb Mamduh Ruimi Nili Najajreh Yousef Ottmann Oliver Mahajna Jamal Ruthardt Martin |
| author_sort | Mian Afsar |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses <it>BCR</it> to <it>ABL</it> resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase “escapes” the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the ‘gatekeeper’ mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.</p> <p>Methods</p> <p>The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.</p> <p>Results</p> <p>Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.</p> <p>Conclusions</p> <p>Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.</p> |
| first_indexed | 2024-12-17T05:08:30Z |
| format | Article |
| id | doaj.art-1218454af5af4a7b92a47c75087b93f2 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-17T05:08:30Z |
| publishDate | 2012-09-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-1218454af5af4a7b92a47c75087b93f22022-12-21T22:02:20ZengBMCBMC Cancer1471-24072012-09-0112141110.1186/1471-2407-12-411Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315IMian AfsarMetodieva AnnaBadura SusanneKhateb MamduhRuimi NiliNajajreh YousefOttmann OliverMahajna JamalRuthardt Martin<p>Abstract</p> <p>Background</p> <p>Chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphatic leukemia (Ph + ALL) are caused by the t(9;22), which fuses <it>BCR</it> to <it>ABL</it> resulting in deregulated ABL-tyrosine kinase activity. The constitutively activated BCR/ABL-kinase “escapes” the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. The ABL-kinase inhibitors (AKIs) Imatinib, Nilotinib or Dasatinib, which target the ATP-binding site, are effective in Ph + leukemia. Another molecular therapy approach targeting BCR/ABL restores allosteric inhibition. Given the fact that all AKIs fail to inhibit BCR/ABL harboring the ‘gatekeeper’ mutation T315I, we investigated the effects of AKIs in combination with the allosteric inhibitor GNF2 in Ph + leukemia.</p> <p>Methods</p> <p>The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.</p> <p>Results</p> <p>Here, we show that GNF-2 increased the effects of AKIs on unmutated BCR/ABL. Interestingly, the combination of Dasatinib and GNF-2 overcame resistance of BCR/ABL-T315I in all models used in a synergistic manner.</p> <p>Conclusions</p> <p>Our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants using a combination of AKIs and allosteric inhibitors.</p>http://www.biomedcentral.com/1471-2407/12/411Philadelphia chromosomeBCR/ABL“gatekeeper” mutation T315IAllosteric inhibitionAbl kinase inhibitorsMolecular therapy |
| spellingShingle | Mian Afsar Metodieva Anna Badura Susanne Khateb Mamduh Ruimi Nili Najajreh Yousef Ottmann Oliver Mahajna Jamal Ruthardt Martin Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I BMC Cancer Philadelphia chromosome BCR/ABL “gatekeeper” mutation T315I Allosteric inhibition Abl kinase inhibitors Molecular therapy |
| title | Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I |
| title_full | Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I |
| title_fullStr | Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I |
| title_full_unstemmed | Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I |
| title_short | Allosteric inhibition enhances the efficacy of ABL kinase inhibitors to target unmutated BCR-ABL and BCR-ABL-T315I |
| title_sort | allosteric inhibition enhances the efficacy of abl kinase inhibitors to target unmutated bcr abl and bcr abl t315i |
| topic | Philadelphia chromosome BCR/ABL “gatekeeper” mutation T315I Allosteric inhibition Abl kinase inhibitors Molecular therapy |
| url | http://www.biomedcentral.com/1471-2407/12/411 |
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