Research on Resistance to Cancer Drug Gleevec

In a study of 11 patients with advanced-stage chronic myeloid leukemia (or Philadelphia chromosome positive acute lymphoid leukemia) who relapsed during treatment with the kinase inhibitor STI-571 (Gleevec), our group reported BCR-ABL gene amplification and kinase domain mutation as potential mechanisms of resistance ([1][1]). Specifically, three patients had gene amplification and six patients had a point mutation resulting in a threonine-to-isoleucine change at amino acid position 315 (T315I) of the ABL kinase domain. Subsequently, Technical Comments were published from two groups (Barthe et al. and Hochhaus et al. ) who reported that they were unable to detect the T315I mutation in such patients ([2][2]). Both groups did, however, detect kinase domain mutations in a different residue in two patients (E255K and E255V). As described in abstracts for the 2001 Annual Meeting of the American Society of Hematology, four groups, including Hochhaus and colleagues ([3][3]), have now detected patients with the T315I mutation ([3][3], [4][4]). All the groups, including ours, have detected additional kinase domain mutations. The overall contribution of these mutations versus other potential resistance mechanisms remains to be defined. 1. [↵][5]1. M. E. Gorre 2. et al. , Science 293, 876 (2001). [OpenUrl][6][Abstract/FREE Full Text][7] 2. [↵][8]1. C. Barthe 2. et al. , Science 293, 2163 (summary) (2001). Full available at ; A. Hochhaus et al., ibid. ; M. E. Gorre et al., ibid. 3. [↵][9]1. S. Kreil 2. et al. , Abstracts for the 43rd Annual Meeting of the American Society of Hematology, Orlando, FL, 7 to 11 December 2001, abstr. 1823. Available at . 4. [↵][10]1. S. Branford 2. et al. , in (3), abstr. 3204; N. Shah et al., . [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #xref-ref-1-1 View reference 1 in text [6]: {openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1062538%26rft_id%253Dinfo%253Apmid%252F11423618%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [7]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIyOTMvNTUzMS84NzYiO3M6NDoiYXRvbSI7czoyNToiL3NjaS8yOTQvNTU0OC8xODM0LjIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [8]: #xref-ref-2-1 View reference 2 in text [9]: #xref-ref-3-1 View reference 3 in text [10]: #xref-ref-4-1 View reference 4 in text