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 - Funding Information:
This work was supported by the David Foundation, funds from the fundraising event ?Sarkomtour? (www.sarkomtour.de), the Deutsche Forschungsgesellschaft (DFG; Grant No. 258480180), GIST Cancer Research Fund (M.C. Heinrich and J.A. Fletcher), a US Veterans Administration Merit Review Grant (I01 BX000338, M.C. Heinrich) and by Blueprint Medicines, European Union (European Regional Development Fund: Investing In Your Future; EFRE-800400), and Drug Discovery Hub Dortmund (DDHD; D. Rauh). The NAVIGATOR trial was fully funded by Blueprint Medicines.
Funding Information:
S. Bauer reports grants and personal fees from Novartis and Blueprint Medicines, personal fees from Deciphera, Bayer, Exelixis, Daichii-Sankyo, Plexxikon, and grants from Incyte during the conduct of the study; personal fees from Pharmamar, ADC Therapeutics, and Lilly outside the submitted work. J. Falkenhorst reports personal fees from Pharmamar and nonfinancial support from Eli Lilly (travel support) outside the submitted work. E. Wardelmann reports personal fees from Nanobiotix, Roche, Lilly, Bristol Myers Squibb, Bayer, and Novartis and grants from Diaceutics during the conduct of the study. H.-U. Schildhaus reports grants from Novartis Oncology, personal fees from Roche, MSD, BMS, Pfizer, and Takeda, and other from Blueprint Medicine outside the submitted work. J.A. Fletcher reports grants from David Foundation during the conduct of the study; personal fees from Deciphera
Funding Information:
This work was supported by the David Foundation, funds from the fundraising event “Sarkomtour” (www.sarkomtour.de), the Deutsche Forschungsgesellschaft (DFG; Grant No. 258480180), GIST Cancer Research Fund (M.C. Heinrich and J.A. Fletcher), a US Veterans Administration Merit Review Grant (I01 BX000338, M.C. Heinrich) and by Blueprint Medicines, European Union (European Regional Development Fund: Investing In Your Future; EFRE-800400), and Drug Discovery Hub Dortmund (DDHD; D. Rauh). The NAVIGATOR trial was fully funded by Blueprint Medicines.
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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UR - http://www.scopus.com/inward/citedby.url?scp=85100236095&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-0487
DO - 10.1158/2159-8290.CD-20-0487
M3 - Article
C2 - 32972961
AN - SCOPUS:85100236095
VL - 11
SP - 108
EP - 125
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 1
ER -