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Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: An imaging, biochemical and molecular modeling study
Author(s) -
Dileo Palma,
Pricl Sabrina,
Tamborini Elena,
Negri Tiziana,
Stacchiotti Silvia,
Gronchi Alessandro,
Posocco Paola,
Laurini Erik,
Coco Paola,
Fumagalli Elena,
Casali Paolo G.,
Pilotti Silvana
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25418
Subject(s) - pdgfra , imatinib , in vivo , gist , cancer research , in silico , imatinib mesylate , tyrosine kinase inhibitor , mutation , exon , medicine , in vitro , pharmacology , biology , stromal cell , cancer , gene , biochemistry , genetics , myeloid leukemia
Beside the well known “ in vivo ” and “ in vitro ” Imatinib resistant D842V mutation in PDGFRA receptor, very few are the information concerning the “ in vivo ” Imatinib activity with respect to the other PDGFRA mutations for which only “ in vitro ” data are available. Two patients carrying PDGFRA mutations in exons 18 (involving residues DIMH842‐845) and 12 (V561D), respectively, were treated with Imatinib at a dose of 400 mg/day. According to Response Evaluation Criteria in Solid Tumors criteria, after a median treatment of 7 months both patients showed clinical partial response, and underwent surgery of the minimal residual disease. Tumor response was confirmed pathologically. In both patients, analyses of PDGFRA performed on pre‐ and/or post‐treatment material were compared to affinity data of the mutated receptor towards the inhibitor. Molecular modeling evidence was found to be consistent with sensitivity of mutated PDGFRA receptors to Imatinib. Thus, the “ in vivo ” evidence that these two mutations of PDGFRA are sensitive to Imatinib was confirmed by a multidimensional approach comprising “ in silico” experiments that, in association to molecular and biochemical analyses, constitutes a powerful tool to predict Imatinib sensitivity, clinically beneficial in the treatment of these tumors with molecularly targeted therapies.