In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 4738-4738
Abstract:
Emergence of resistance is a major concern when treating cancer patients with targeted kinase inhibitors, as exemplified by the appearance of point mutations in Bcr-Abl in CML patients treated with imatinib or a secondary EGFR-T790M mutation in lung cancer patients treated with gefitinib or erlotinib. In vitro approaches to identify resistance mutations in Bcr-Abl have yielded mutation spectra that faithfully recapitulated clinical observations. In order to predict resistance mutations in the receptor tyrosine kinase c-Met that could emerge during inhibitor treatment in patients, we performed a resistance screen in BaF3 cells transformed with Tpr-Met using the novel selective c-Met inhibitor NVP-BVU972. The observed spectrum of mutations in resistant cells was dominated by substitutions of the residue Y1230 in the activation loop of the c-Met kinase domain, but also included other missense mutations. Intriguingly, some of the c-Met resistance mutations observed in this cellular screen were identical with previously described activating mutations in cancer patients that interfere with inhibitory interactions in the inactive conformation. Co-crystallization of the c-Met kinase domain in complex with NVP-BVU972 revealed a key role for Y1230 in binding of NVP-BVU972. This binding mode has also been reported for multiple other selective c-Met inhibitors, some of which have entered clinical trials, suggesting a broader relevance of the resistance profile obtained with NVP-BVU972. A second resistance screen in the same format with the c-Met inhibitor AMG 458 yielded a distinct spectrum of mutations that was rich in F1200 alterations. This is consistent with a different predicted binding mode. Again, the mutation profile observed with AMG 458 could be predictive for several other inhibitors that bind c-Met in a similar way. Collectively, our findings suggest that amino acid substitutions in the c-Met kinase domain of cancer patients need to be carefully monitored prior to and during treatment with c-Met inhibitors, as resistance may pre-exist or emerge. Compounds binding in the same manner as NVP-BVU972 might be particularly susceptible to the development of resistance through mutations in Y1230, a complication that could potentially be overcome by c-Met inhibitors with alternative binding modes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2011-4738
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-4738
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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