Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
- Publication type:
- Journal article
- Metadata:
-
- Abstract
- <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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 avapritinib 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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1</jats:p> </jats:sec>
- Autoren
- Susanne Grunewald
- Lillian R Klug
- Thomas Mühlenberg
- Jonas Lategahn
- Johanna Falkenhorst
- Ajia Town
- Christiane Ehrt
- Eva Wardelmann
- Wolfgang Hartmann
- Hans-Ulrich Schildhaus
- Juergen Treckmann
- Jonathan A Fletcher
- Sascha Jung
- Paul Czodrowski
- Stephen Miller
- Oleg Schmidt-Kittler
- Daniel Rauh
- Michael C Heinrich
- Sebastian Bauer
- DOI
- 10.1158/2159-8290.cd-20-0487
- eISSN
- 2159-8290
- ISSN
- 2159-8274
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Cancer Discovery
- Sprache
- en
- Online publication date
- 2021
- Paginierung
- 108 - 125
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Herausgeber
- American Association for Cancer Research (AACR)
- Herausgeber URL
- http://dx.doi.org/10.1158/2159-8290.cd-20-0487
- Datum der Datenerfassung
- 2022
- Titel
- Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
- Ausgabe der Zeitschrift
- 11
Data source: Crossref
- Other metadata sources:
-
- Abstract
- Gastrointestinal stromal tumors (GIST) harboring activating mutations of <i>PDGFRA</i> 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 <i>PDGFRA</i>-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with <i>PDGFRA</i> primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within <i>PDGFRA</i> exons 13, 14, and 15 that interfere with avapritinib binding. Secondary <i>PDGFRA</i> 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. SIGNIFICANCE: Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.<i>This article is highlighted in the In This Issue feature, p. 1</i>.
- Addresses
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany.
- Autoren
- Susanne Grunewald
- Lillian R Klug
- Thomas Mühlenberg
- Jonas Lategahn
- Johanna Falkenhorst
- Ajia Town
- Christiane Ehrt
- Eva Wardelmann
- Wolfgang Hartmann
- Hans-Ulrich Schildhaus
- Juergen Treckmann
- Jonathan A Fletcher
- Sascha Jung
- Paul Czodrowski
- Stephen Miller
- Oleg Schmidt-Kittler
- Daniel Rauh
- Michael C Heinrich
- Sebastian Bauer
- DOI
- 10.1158/2159-8290.cd-20-0487
- eISSN
- 2159-8290
- Externe Identifier
- PubMed Identifier: 32972961
- Funding acknowledgements
- BLRD VA: I01 BX005358
- Deutsche Forschungsgesellschaft: 258480180
- BLRD VA: I01 BX000338
- European Regional Development Fund: EFRE-800400
- US Veterans Administration Merit Review: I01 BX000338
- Open access
- false
- ISSN
- 2159-8274
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Cancer discovery
- Schlüsselwörter
- Humans
- Gastrointestinal Stromal Tumors
- Pyrazoles
- Pyrroles
- Triazines
- Receptor, Platelet-Derived Growth Factor alpha
- Mutation
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2020
- Paginierung
- 108 - 125
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum der Datenerfassung
- 2020
- Titel
- Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain.
- Sub types
- Comment
- Research Support, Non-U.S. Gov't
- Journal Article
- Research Support, N.I.H., Extramural
- Ausgabe der Zeitschrift
- 11
Data source: Europe PubMed Central
- Abstract
- 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 avapritinib 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. SIGNIFICANCE: Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.This article is highlighted in the In This Issue feature, p. 1.
- Date of acceptance
- 2020
- Autoren
- Susanne Grunewald
- Lillian R Klug
- Thomas Mühlenberg
- Jonas Lategahn
- Johanna Falkenhorst
- Ajia Town
- Christiane Ehrt
- Eva Wardelmann
- Wolfgang Hartmann
- Hans-Ulrich Schildhaus
- Juergen Treckmann
- Jonathan A Fletcher
- Sascha Jung
- Paul Czodrowski
- Stephen Miller
- Oleg Schmidt-Kittler
- Daniel Rauh
- Michael C Heinrich
- Sebastian Bauer
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/32972961
- DOI
- 10.1158/2159-8290.CD-20-0487
- eISSN
- 2159-8290
- Funding acknowledgements
- BLRD VA: I01 BX000338
- BLRD VA: I01 BX005358
- Ausgabe der Veröffentlichung
- 1
- Zeitschrift
- Cancer Discov
- Schlüsselwörter
- Gastrointestinal Stromal Tumors
- Humans
- Mutation
- Pyrazoles
- Pyrroles
- Receptor, Platelet-Derived Growth Factor alpha
- Triazines
- Sprache
- eng
- Country
- United States
- Paginierung
- 108 - 125
- PII
- 2159-8290.CD-20-0487
- Datum der Veröffentlichung
- 2021
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2021
- Titel
- Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain.
- Sub types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 11
Data source: PubMed
- Beziehungen:
-