Resistance to TRK inhibition mediated by convergent MAPK pathway activation

Cocco, Emiliano; Schram, Alison M.; Kulick, Amanda; Misale, Sandra; Won, Helen; Yaeger, Rona; Razavi, Pedram; Ptashkin, Ryan; Hechtman, Jaclyn F.; Toska, Eneda; Cownie, James; Somwar, Romel; Shifman, Sophie; Mattar, Marissa S.; Selcuklu, S. Duygu; Samoila, Aliaksandra; Guzman, Sean; Tuch, Brian B.; Ebata, Kevin; Stanchina, Elisa de; Nagy, Rebecca J.; Lanman, Richard B.; Houck-Loomis, Brian; Patel, Juber; Berger, Michael F.; Ladanyi, Marc; Hyman, David M.; Drilon, Alexander; Scaltriti, Maurizio

doi:10.1038/s41591-019-0542-z

Cited by 166 publications

(161 citation statements)

References 39 publications

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“…Finally, the optimal strategy for molecular profiling at disease progression after NTRK fusions-targeting should now be investigated. Present data suggest efficacy of liquid-based assessment, but given the wide range of both on-target and off-target resistance mechanisms, comprehensive assays seem to be necessary [156].…”

Section: Dna and Rna Molecular Testingmentioning

confidence: 88%

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NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

Gambella

Senetta

Collemi

et al. 2020

IJMS

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The neurotrophic tropomyosin receptor kinase (NTRK) genes (NTRK1, NTRK2, and NTRK3) code for three transmembrane high-affinity tyrosine-kinase receptors for nerve growth factors (TRK-A, TRK-B, and TRK-C) which are mainly involved in nervous system development. Loss of function alterations in these genes can lead to nervous system development problems; conversely, activating alterations harbor oncogenic potential, promoting cell proliferation/survival and tumorigenesis. Chromosomal rearrangements are the most clinically relevant alterations of pathological NTRK activation, leading to constitutionally active chimeric receptors. NTRK fusions have been detected with extremely variable frequencies in many pediatric and adult cancer types, including central nervous system (CNS) tumors. These alterations can be detected by different laboratory assays (e.g., immunohistochemistry, FISH, sequencing), but each of these approaches has specific advantages and limitations which must be taken into account for an appropriate use in diagnostics or research. Moreover, therapeutic targeting of this molecular marker recently showed extreme efficacy. Considering the overall lack of effective treatments for brain neoplasms, it is expected that detection of NTRK fusions will soon become a mainstay in the diagnostic assessment of CNS tumors, and thus in-depth knowledge regarding this topic is warranted.

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Section: Dna and Rna Molecular Testingmentioning

confidence: 88%

“…Examples of this resistance mechanism are the acquisition of the BRAF V600E or KRAS G12D mutations or MET amplification. Of note, in these cases, prompt treatment with drugs targeting the new resistance-related alterations enabled new tumor responses [156].…”

Section: Resistance Mechanisms To First-generation Ntrk Inhibitorsmentioning

confidence: 99%

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

Gambella

Senetta

Collemi

et al. 2020

IJMS

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“…The ERK pathway is activated in approximately 30% of all human cancers via RAS-, BRAF-, or MAP2K1 (MEK1)-activating mutations and thus has attracted significant interest as a therapeutic cancer target (3). In addition, alterations known to activate the ERK pathway are also common in acquired resistance to BRAF, MEK, ALK, CDK4/6, TRKA, and EGFR inhibitors (4)(5)(6). Therefore, targeting ERK1/2 in the ERK pathway is an attractive strategy for the treatment of a variety of tumor types harboring ERK pathway alterations.…”

Section: Introductionmentioning

confidence: 99%

ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine

Bhagwat

McMillen

Cai

et al. 2020

Molecular Cancer Therapeutics

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The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF-and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAFand KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

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“…The mutations flank the ATP binding pocket and all cause hyperphosphorylation of MEK1/2 and ERK1/2. Combination therapy of dabrafenib and other inhibitors of the MAPK pathway (e.g., trametinib a MEK inhibitor) [442] leads to mutation in other genes in the pathway such as MEK2 or NRAS [443]. For a more comprehensive review of MAPK pathway resistant mutations please see [444].…”

Section: Classificationmentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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Resistance to TRK inhibition mediated by convergent MAPK pathway activation

Cited by 166 publications

References 39 publications

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

ERK Inhibitor LY3214996 Targets ERK Pathway–Driven Cancers: A Therapeutic Approach Toward Precision Medicine

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

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