Resistance to TRK inhibition mediated by convergent MAPK pathway activation Research Letter
| Authors: | Cocco, E.; Schram, A. M.; Kulick, A.; Misale, S.; Won, H. H.; Yaeger, R.; Razavi, P.; Ptashkin, R.; Hechtman, J. F.; Toska, E.; Cownie, J.; Somwar, R.; Shifman, S.; Mattar, M.; Selçuklu, S. D.; Samoila, A.; Guzman, S.; Tuch, B. B.; Ebata, K.; de Stanchina, E.; Nagy, R. J.; Lanman, R. B.; Houck-Loomis, B.; Patel, J. A.; Berger, M. F.; Ladanyi, M.; Hyman, D. M.; Drilon, A.; Scaltriti, M. |
| Title: | 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. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | mitogen activated protein kinase; controlled study; human tissue; unclassified drug; gene mutation; human cell; missense mutation; cancer combination chemotherapy; cancer growth; nonhuman; pancreas cancer; letter; colorectal cancer; mouse; animal tissue; enzyme inhibition; gene amplification; animal experiment; animal model; tumor biopsy; enzyme activation; protein tyrosine kinase; cancer resistance; dna; pancreas adenocarcinoma; bile duct carcinoma; oncogene k ras; b raf kinase; mitogen activated protein kinase kinase; crizotinib; ectopic expression; dabrafenib; trametinib; mapk signaling; off-target effect; human; male; female; priority journal; entrectinib; larotrectinib; circulating cell free dna; selitrectinib |
| Journal Title: | Nature Medicine |
| Volume: | 25 |
| Issue: | 9 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2019-09-01 |
| Start Page: | 1422 |
| End Page: | 1427 |
| Language: | English |
| DOI: | 10.1038/s41591-019-0542-z |
| PUBMED: | 31406350 |
| PROVIDER: | scopus |
| PMCID: | PMC6736691 |
| DOI/URL: | |
| Notes: | Letter -- Export Date: 1 November 2019 -- Source: Scopus |
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