title: p.(L576P) -KIT mutation in GIST: Favorable prognosis and sensitive to imatinib?
abstract: Exon 11 KIT mutations are found in a majority of gastrointestinal stromal tumors (GIST) and are usually predictive of response to imatinib, a KIT, PDGFRA and ABL inhibitor. Exon 11 mutations with poor sensitivity to imatinib and poor outcome can be observed on rare occasions, including p.(L576P). In silico and in vitro studies suggested a decreased binding affinity for imatinib in p.(L576P) KIT mutations, thereby offering an explanation for their poor outcome and poor response to standard therapy. These observations were further corroborated with anecdotal case reports of refractoriness or non-durable response to imatinib therapy. However, we describe the favorable response to imatinib and outcome in 5 p.(L576P)-KIT mutant GIST patients treated at a tertiary sarcoma referral center. The sensitivity of p.(L576P)-KIT mutations to imatinib, and the prognostic impact of this mutation need to be further evaluated in a larger cohort. Based on our observations, p.(L576P) mutated GISTs should be treated with standard first line imatinib therapy.
authors.affiliation: a Sarcoma Unit, Royal Marsden NHS Foundation Trust , London , UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Noujaim
authors.affiliation: b The Centre for Molecular Pathology, Royal Marsden NHS Foundation Trust , London , UK.
authors.forename: David
authors.initials: D
authors.lastname: Gonzalez
authors.affiliation: a Sarcoma Unit, Royal Marsden NHS Foundation Trust , London , UK.
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.affiliation: a Sarcoma Unit, Royal Marsden NHS Foundation Trust , London , UK.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Jones
authors.affiliation: a Sarcoma Unit, Royal Marsden NHS Foundation Trust , London , UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Judson
mesh_terms: D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D011379:Prognosis
chemical_list: D000068877:Imatinib Mesylate
keywords: Dasatinib; GIST; L576P; imatinib; mutation