TRK XDFG mutations trigger a sensitivity switch from type i to ii kinase inhibitors

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

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 drug binding by generating steric hin-drance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leverag-ing inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion–positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation.

Original languageEnglish
Pages (from-to)126-141
Number of pages16
JournalCancer Discovery
Volume11
Issue number1
DOIs
StatePublished - 1 Jan 2021

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