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Resistance to TRK inhibition mediated by convergent MAPK pathway activation.

Abstract：

:TRK fusions are found in a variety of cancer types, lead to oncogenic addiction, and strongly predict tumor-agnostic efficacy of TRK inhibition1-8. With the recent approval of the first selective TRK inhibitor, larotrectinib, for patients with any TRK-fusion-positive adult or pediatric solid tumor, to identify mechanisms of treatment failure after initial response has become of immediate therapeutic relevance. So far, the only known resistance mechanism is the acquisition of on-target TRK kinase domain mutations, which interfere with drug binding and can potentially be addressable through second-generation TRK inhibitors9-11. Here, we report off-target resistance in patients treated with TRK inhibitors and in patient-derived models, mediated by genomic alterations that converge to activate the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway-directed targeted therapy, administered alone or in combination with TRK inhibition, re-established disease control. Experimental modeling further suggests that upfront dual inhibition of TRK and MEK may delay time to progression in cancer types prone to the genomic acquisition of MAPK pathway-activating alterations. Collectively, these data suggest that a subset of patients will develop off-target mechanisms of resistance to TRK inhibition with potential implications for clinical management and future clinical trial design.

journal_name

Nat Med

journal_title

Nature medicine

authors

Cocco E,Schram AM,Kulick A,Misale S,Won HH,Yaeger R,Razavi P,Ptashkin R,Hechtman JF,Toska E,Cownie J,Somwar R,Shifman S,Mattar M,Selçuklu SD,Samoila A,Guzman S,Tuch BB,Ebata K,de Stanchina E,Nagy RJ,Lanman RB,

doi

10.1038/s41591-019-0542-z

subject

Has Abstract

pub_date

2019-09-01 00:00:00

pages

1422-1427

issue

9

eissn

1078-8956

issn

1546-170X

pii

10.1038/s41591-019-0542-z

journal_volume

25

pub_type

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