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PDBsum entry 3zbf
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References listed in PDB file
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Key reference
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Title
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Acquired resistance to crizotinib from a mutation in cd74-Ros1.
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Authors
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M.M.Awad,
R.Katayama,
M.Mctigue,
W.Liu,
Y.L.Deng,
A.Brooun,
L.Friboulet,
D.Huang,
M.D.Falk,
S.Timofeevski,
K.D.Wilner,
E.L.Lockerman,
T.M.Khan,
S.Mahmood,
J.F.Gainor,
S.R.Digumarthy,
J.R.Stone,
M.Mino-Kenudson,
J.G.Christensen,
A.J.Iafrate,
J.A.Engelman,
A.T.Shaw.
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Ref.
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N Engl J Med, 2013,
368,
2395-2401.
[DOI no: ]
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PubMed id
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Abstract
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Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently
shown efficacy in the treatment of lung cancers with ROS1 translocations.
Resistance to crizotinib developed in a patient with metastatic lung
adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a
dramatic response to treatment. We performed a biopsy of a resistant tumor and
identified an acquired mutation leading to a glycine-to-arginine substitution at
codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the
gatekeeper residue, it confers resistance to ROS1 kinase inhibition through
steric interference with drug binding. The same resistance mutation was observed
at all the metastatic sites that were examined at autopsy, suggesting that this
mutation was an early event in the clonal evolution of resistance. (Funded by
Pfizer and others; ClinicalTrials.gov number, NCT00585195 .).
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