Imatinib response in two GIST patients carrying two hitherto functionally uncharacterized PDGFRA mutations: an imaging, biochemical and molecular modeling study.
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.
Dileo
Palma
P
Department of Medical Oncology, SS Trattamento Medico dei Sarcomi dell'Adulto, Fondazione IRCCS - Istituto Nazionale Tumori, Milano, Italy. palma.dileo@istitutotumori.mi.it
Pricl
Sabrina
S
Tamborini
Elena
E
Negri
Tiziana
T
Stacchiotti
Silvia
S
Gronchi
Alessandro
A
Posocco
Paola
P
Laurini
Erik
E
Coco
Paola
P
Fumagalli
Elena
E
Casali
Paolo G
PG
Pilotti
Silvana
S
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D010879:Piperazines / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D011379:Prognosis; D011487:Protein Conformation; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000737:chemistry / Q000235:genetics*; D014057:Tomography, X-Ray Computed
D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha