A Drug Resistance Screen Using a Selective MET Inhibitor Reveals a Spectrum of Mutations That Partially Overlap with Activating Mutations Found in Cancer Patients
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Tiedt, Ralph, Degenkolbe, Elisa, Furet, Pascal, Appleton, Brent, Schoepfer, Joseph, Ruddy, David, Monahan, John, Blank, Jutta, Haasen, Dorothea, Drueckes, Peter, Wartmann, Markus, Mccarthy, Clive and Hofmann, Francesco (2011) A Drug Resistance Screen Using a Selective MET Inhibitor Reveals a Spectrum of Mutations That Partially Overlap with Activating Mutations Found in Cancer Patients. Cancer Research, 71 (15). pp. 5255-5264. ISSN 0008-5472
Abstract
The emergence of drug resistance is a primary concern in any cancer treatment, including with targeted kinase
inhibitors as exemplified by the appearance of Bcr-Abl point mutations in chronic myeloid leukemia (CML)
patients treated with imatinib. In vitro approaches to identify resistance mutations in Bcr-Abl have yielded
mutation spectra that faithfully recapitulated clinical observations. To predict resistance mutations in the receptor
tyrosine kinaseMETthat could emerge during inhibitor treatment in patients, we conducted a resistance screen in
BaF3 TPR-METcells using the novel selectiveMETinhibitor NVP-BVU972. The observed spectrumof mutations in
resistant cells was dominated by substitutions of tyrosine 1230 but also included other missense mutations and
partially overlapped with activating MET mutations that were previously described in cancer patients. Cocrystallization
of the MET kinase domain in complex with NVP-BVU972 revealed a key role for Y1230 in binding of
NVP-BVU972, as previously reported for multiple other selective MET inhibitors. A second resistance screen in
the same format with the MET inhibitor AMG 458 yielded a distinct spectrum of mutations rich in F1200
alterations, which is consistent with a different predicted binding mode. Our findings suggest that amino acid
substitutions in the MET kinase domain of cancer patients need to be carefully monitored before and during
treatment with MET inhibitors, as resistance may preexist 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
condition that may be addressed by MET inhibitors with alternative binding modes.
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/3698 |