TY - JOUR
T1 - Resistance to avapritinib in pdgfra-driven gist is caused by secondary mutations in the pdgfra kinase domain
AU - Grunewald, Susanne
AU - Klug, Lillian R.
AU - Mühlenberg, Thomas
AU - Lategahn, Jonas
AU - Falkenhorst, Johanna
AU - Town, Ajia
AU - Ehrt, Christiane
AU - Wardelmann, Eva
AU - Hartmann, Wolfgang
AU - Schildhaus, Hans Ulrich
AU - Treckmann, Juergen
AU - Fletcher, Jonathan A.
AU - Jung, Sascha
AU - Czodrowski, Paul
AU - Miller, Stephen
AU - Schmidt-Kittler, Oleg
AU - Rauh, Daniel
AU - Heinrich, Michael C.
AU - Bauer, Sebastian
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1
Y1 - 2021/1
N2 - Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapri-tinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance.
AB - Gastrointestinal stromal tumors (GIST) harboring activating mutations of PDGFRA respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of PDGFRA-mutant patients treated with avapri-tinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with PDGFRA primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within PDGFRA exons 13, 14, and 15 that interfere with avapritinib binding. Secondary PDGFRA mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance.
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U2 - 10.1158/2159-8290.CD-20-0487
DO - 10.1158/2159-8290.CD-20-0487
M3 - Article
C2 - 32972961
AN - SCOPUS:85100236095
SN - 2159-8274
VL - 11
SP - 108
EP - 125
JO - Cancer discovery
JF - Cancer discovery
IS - 1
ER -