TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.

doi:10.1158/2159-8290.CD-20-0571

Loading publication...

Noodle always counts identifier-free feature events for service operation. With your permission, Google Analytics can also estimate audience and engagement. Search text, publication identifiers, cookies, IP addresses and browser fingerprints are never included in Noodle's first-party event counters.

Privacy details

Community

Back to search

Article

TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.

Cancer discovery - 1 Jan 2021

Cocco Emiliano, Lee Ji Eun, Kannan Srinivasaraghavan, Schram Alison M, Won Helen H, Shifman Sophie, Kulick Amanda, Baldino Laura, Toska Eneda, Arruabarrena-Aristorena Amaia, Kittane Srushti, Wu Fan, Cai Yanyan, Arena Sabrina, Mussolin Benedetta, Kannan Ram, Vasan Neil, Gorelick Alexander N, Berger Michael F, Novoplansky Ofra, Jagadeeshan Sankar, Liao Yi, Rix Uwe, Misale Sandra, Taylor Barry S, Bardelli Alberto, Hechtman Jaclyn F, Hyman David M, Elkabets Moshe, de Stanchina Elisa, Verma Chandra S, Ventura Andrea, Drilon Alexander, Scaltriti Maurizio

Abstract excerpt

On-target resistance to next-generation TRK inhibitors in TRK fusion-positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKAG667 and TRKCG696 xDFG substitutions reduce...

Read the complete abstract on PubMed

Topics

Share this publication in a Topic to start or enrich a Post.

Share to Cancer Mechanisms and Therapy

Methodology Data sources Editorial policy Privacy About Contact Helena Bioinformatics

Share to Lung Cancer Treatments and Mutations

Share to Melanoma and MAPK Pathways

Share to Mutation

Share to Neoplasms

Share to Oncogenes

Share to Protein Kinase Inhibitors

Share to Receptor, trkA

Source

Open in PubMed Open full text

Identifiers

PMID: 33004339
DOI: 10.1158/2159-8290.CD-20-0571
PMCID: PMC8012405

Provenance

PubMed metadata and Literature Corpus relationships. Corpus snapshot updated 2 Sept 2026.

Related research

Semantic proximity does not establish scientific evidence.

Research trail→

Click a neighbor to travelStep 1 · 12 closest

TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors.PMID 33004339Read ↗

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy.Semantic proximity Read ↗

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinibSemantic proximity Read ↗

The resistance tetrad: amino acid hotspots for kinome-wide exploitation of drug-resistant protein kinase alleles.Semantic proximity Read ↗

NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors.Semantic proximity Read ↗

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo.Semantic proximity Read ↗

Overcoming Secondary Mutations of Type II Kinase Inhibitors.Semantic proximity Read ↗

Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation.Semantic proximity Read ↗

A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid TumorsSemantic proximity Read ↗

Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance.Semantic proximity Read ↗

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.Semantic proximity Read ↗

Discovery of Next-Generation Tropomyosin Receptor Kinase (TRK) Inhibitors for Combatting Resistance Associated with Protein MutationSemantic proximity Read ↗

Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants.Semantic proximity Read ↗

⌁Select a neighboring publication to make it the new centre.