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:
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.
Funding Information:
Pharmaceuticals and Novartis outside the submitted work; in addition, Dr Fletcher has a patent for activating mutations of PDGFRA issued and a patent for Treatment of Gastrointestinal Stromal Tumors licensed to Novartis. S. Miller reports personal fees from Blueprint Medicines (employee of Blueprint Medicines) and other from Blueprint Medicines (own stock in Blueprint Medicines) outside the submitted work. O. Schmidt-Kittler reports personal fees from Blueprint Medicines (employee and shareholder of Blueprint Medicines) during the conduct of the study; personal fees from Blueprint Medicines (employee and shareholder of Blueprint Medicines) outside the submitted work. D. Rauh reports grants from DFG (research grant by the German government) during the conduct of the study; other from PearlRiver Bio GmbH (cofounder and shareholder), CDL Therapeutics GmbH (co-founder and shareholder), and Pfizer, AZ, Sanofi, BI, and Bayer (consulting and lecture fees) outside the submitted work. M.C. Heinrich reports grants from US Veterans Administration (I01 BX000338), Jonathan David Foundation, and GIST Cancer Research Fund, personal fees from Molecular MD and Blueprint Medicines during the conduct of the study; personal fees from Deciphera Pharmaceuticals and personal fees from Novartis outside the submitted work; in addition, Dr Heinrich has a patent for Treatment of Gastrointestinal Stromal Tumors issued, licensed, and with royalties paid from Novartis and a patent for activating mutations of PDGFRA issued. J. Lategahn reports personal fees from PearlRiver Bio GmbH (Dr Lategahn is shareholder and full-time employee of PearlRiver Bio GmbH) outside the submitted work. No disclosures were reported by the other authors.
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.
UR - http://www.scopus.com/inward/record.url?scp=85100236095&partnerID=8YFLogxK
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 -