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SHR Neuro Cancer Cardio Lipid Metab Microb

Liegl, B; Kepten, I; Le, C; Zhu, M; Demetri, GD; Heinrich, MC; Fletcher, CD; Corless, CL; Fletcher, JA.
Heterogeneity of kinase inhibitor resistance mechanisms in GIST.
J Pathol. 2008; 216(1): 64-74. Doi: 10.1002/path.2382 [OPEN ACCESS]
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Leading authors Med Uni Graz: Liegl-Atzwanger Bernadette
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Abstract:: Most GIST patients develop clinical resistance to KIT/PDGFRA tyrosine kinase inhibitors (TKI). However, it is unclear whether clinical resistance results from single or multiple molecular mechanisms in each patient. KIT and PDGFRA mutations were evaluated in 53 GIST metastases obtained from 14 patients who underwent surgical debulking after progression on imatinib or sunitinib. To interrogate possible resistance mechanisms across a broad biological spectrum of GISTs, inter- and intra-lesional heterogeneity of molecular drug-resistance mechanisms were evaluated in the following: conventional KIT (CD117)-positive GISTs with KIT mutations in exon 9, 11 or 13; KIT-negative GISTs; GISTs with unusual morphology; and KIT/PDGFRA wild-type GISTs. Genomic KIT and PDGFRA mutations were characterized systematically, using complementary techniques including D-HPLC for KIT exons 9, 11-18 and PDGFRA exons 12, 14, 18, and mutation-specific PCR (V654A, D820G, N822K, Y823D). Primary KIT oncogenic mutations were found in 11/14 patients (79%). Of these, 9/11 (83%), had secondary drug-resistant KIT mutations, including six (67%) with two to five different secondary mutations in separate metastases, and three (34%) with two secondary KIT mutations in the same metastasis. The secondary mutations clustered in the KIT ATP binding pocket and kinase catalytic regions. FISH analyses revealed KIT amplicons in 2/10 metastases lacking secondary KIT mutations. This study demonstrates extensive intra- and inter-lesional heterogeneity of resistance mutations and gene amplification in patients with clinically progressing GIST. KIT kinase resistance mutations were not found in KIT/PDGFRA wild-type GISTs or in KIT-mutant GISTs showing unusual morphology and/or loss of KIT expression by IHC, indicating that resistance mechanisms are fundamentally different in these tumours. Our observations underscore the heterogeneity of clinical TKI resistance, and highlight the therapeutic challenges involved in salvaging patients after clinical progression on TKI monotherapies.
Find related publications in this database (using NLM MeSH Indexing): Aged -; Antineoplastic Agents - therapeutic use; Drug Resistance, Neoplasm - drug effects; Female -; Gastrointestinal Stromal Tumors - drug therapy; Humans -; Indoles - therapeutic use; Male -; Middle Aged -; Piperazines - therapeutic use; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - therapeutic use; Pyrroles - therapeutic use
Find related publications in this database (Keywords): imatinib; sunitinib; drug resistance mechanisms; GIST; heterogeneity