Journal
CANCER DISCOVERY
Volume 11, Issue 1, Pages 126-141Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0571
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Funding
- National Cancer Institute (NCI) under MSK Cancer Center Support Grant/Core Grant [P30 CA008748, R01CA226864]
- Cycle for Survival
- Nonna's Garden Foundation
- NIH [T32 CA009207, 5 T32 CA160001-08]
- ASCO Young Investigator Award
- Geoffrey Beene Cancer Research Foundation
- STARR Foundation
- Pershing Square Cancer Research Foundation
- MSK Society Scholars Prize
- A*STAR (IAF-PP grant) [H18/01/a0/015]
- National Supercomputing Centre, Singapore
- United States-Israel Binational Science Foundation [2017323]
- Fondazione AIRC under the 5 per Mille 2018 [21091]
- AIRC IG 2018 [21923]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per Mille 2014 e 2015 Ministero della
- AIRC under MFAG 2017 [20236]
- [R01CA181746]
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This study reveals that TRK xDFG mutations in TRK fusion-positive cancers confer resistance to type I TRK inhibitors but may serve as a potential biomarker for the activity of type II TRK inhibitors, which should be the focus of rational drug design.
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.
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