2. Academic Validation
  3. TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors

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

  • Cancer Discov. 2021 Jan;11(1):126-141. doi: 10.1158/2159-8290.CD-20-0571.
Emiliano Cocco 1 2,  Ji Eun Lee  # 3,  Srinivasaraghavan Kannan  # 4,  Alison M Schram  # 5 6,  Helen H Won 7,  Sophie Shifman 8 2,  Amanda Kulick 9,  Laura Baldino 8 2,  Eneda Toska 8,  Amaia Arruabarrena-Aristorena 8,  Srushti Kittane 8,  Fan Wu 8,  Yanyan Cai 8,  Sabrina Arena 10 11,  Benedetta Mussolin 11,  Ram Kannan 3,  Neil Vasan 8,  Alexander N Gorelick 8 12,  Michael F Berger 8 2 7,  Ofra Novoplansky 13,  Sankar Jagadeeshan 13,  Yi Liao 14,  Uwe Rix 14,  Sandra Misale 15,  Barry S Taylor 12,  Alberto Bardelli 10 11,  Jaclyn F Hechtman 2,  David M Hyman 5 6,  Moshe Elkabets 13,  Elisa de Stanchina 9,  Chandra S Verma 16 17 18,  Andrea Ventura 19,  Alexander Drilon 20 6,  Maurizio Scaltriti 1 2
Affiliations

Affiliations

  • 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected] [email protected] [email protected] [email protected] [email protected].
  • 2 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 3 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 4 Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore.
  • 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 6 Weill Cornell Medical College, New York, New York.
  • 7 Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 8 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 9 Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 10 Department of Oncology, University of Torino, Candiolo, Torino, Italy.
  • 11 Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
  • 12 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 13 The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
  • 14 Department of Drug Discovery, Moffitt Cancer Center, Tampa, Florida.
  • 15 Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 16 Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore. [email protected] [email protected] [email protected] [email protected] [email protected].
  • 17 School of Biological Sciences, Nanyang Technological University, Singapore.
  • 18 Department of Biological Sciences, National University of Singapore, Singapore.
  • 19 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected] [email protected] [email protected] [email protected] [email protected].
  • 20 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. [email protected] [email protected] [email protected] [email protected] [email protected].
  • # Contributed equally.
PMID: 33004339 DOI: 10.1158/2159-8290.CD-20-0571
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 hindrance. 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 leveraging 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.This article is highlighted in the In This Issue feature, p. 1.

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