Dissecting Therapeutic Resistance to ERK Inhibition

Jha, Sharda; Morris, Erick; Hruza, Alan; Mansueto, My Sam; Schroeder, Gottfried K.; Arbanas, Jaren; McMasters, Daniel R.; Restaino, Clifford R.; Dayananth, Priya; Black, Stuart; Elsen, Nathaniel L.; Mannarino, Anthony P.; Cooper, Alan; Zawel, Leigh; Jayaraman, Lata; Samatar, Ahmed A.

doi:10.1158/1535-7163.mct-15-0172

Cited by 49 publications

(44 citation statements)

References 32 publications

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“…A study using random mutagenesis, identified some of the on-target ERK mutations that confer resistance to V11e (36). Consistent with our findings, a recent study involving S984 ERKi identified the G186D ERK1 mutation in HCT116 cells as a cause of resistance to S984 (37). Structural analysis of the ERK indicated that the mutations affect the binding of ERK-inhibitors and thus prevent them from blocking ERK activity.…”

Section: Discussionsupporting

confidence: 88%

“…S3A). Consistent with our findings, expression of ERK1 and ERK2 mutants were previously reported to confer ERKi resistance in A375 and HCT116 cells (36,37,61). These findings confirm that the on-target mutations are sufficient to confer resistance to ERK inhibitors against which they arose.…”

Section: Erk1/2 Mutant Erki-r Cells Are Sensitive To An Alternate Erksupporting

confidence: 92%

“…An A191V mutation in MIA PaCa2-VI-3-R and G186D mutation in HCT116-S984-R were found in ERK1 ( (36). Recently, a G186D ERK1 mutation was reported in S984 resistant HCT116 cells (37).…”

Section: On-target Erk Mutations Confer Resistance To Erk Inhibitorsmentioning

confidence: 97%

“…In this study we tested five structurally different ATP-competitive ERK inhibitors (ERKi- (33,37,57) (Supplementary Fig. 1A).…”

Section: Sustained Inhibition Of Erk In Ras/raf-mutant Cells Leads Tomentioning

confidence: 99%

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ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

Jaiswal¹,

Durinck²,

Stawiski³

et al. 2018

Clinical Cancer Research

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Results:We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERBB2 as mechanisms of acquired resistance. Structural analysis of ERK showed that specific compounds that induced on-target ERK mutations were impaired in their ability to bind mutant ERK. We show that in addition to MEK inhibitor, ERBB-receptor and PI3K/mTOR pathway inhibitors are effective in overcoming ERK-inhibitor resistance.Conclusions: These findings suggest that combination therapy with MEK or ERBB-receptor or PI3K/mTOR and ERK inhibitors may be an effective strategy for managing the emergence of resistance in the clinic. Author Manuscript Published OnlineFirst on May 14, 2018; DOI: 10.1158/1078 3 Translational Relevance:Acquired resistance to targeted therapy is a major challenge. ERK inhibitors are under investigation for treatment of RAF/RAS mutated tumors or those resistant to BRAF/MEK inhibitors. Understanding the evolution of resistance to current ERK inhibitors will help guide in developing better inhibitors and also aid in identifying strategies for combination therapy that can overcome clinical resistance development.

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Section: Discussionsupporting

confidence: 88%

Section: Erk1/2 Mutant Erki-r Cells Are Sensitive To An Alternate Erksupporting

confidence: 92%

“…An A191V mutation in MIA PaCa2-VI-3-R and G186D mutation in HCT116-S984-R were found in ERK1 ( (36). Recently, a G186D ERK1 mutation was reported in S984 resistant HCT116 cells (37).…”

Section: On-target Erk Mutations Confer Resistance To Erk Inhibitorsmentioning

confidence: 97%

“…In this study we tested five structurally different ATP-competitive ERK inhibitors (ERKi- (33,37,57) (Supplementary Fig. 1A).…”

Section: Sustained Inhibition Of Erk In Ras/raf-mutant Cells Leads Tomentioning

confidence: 99%

See 2 more Smart Citations

ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

Jaiswal¹,

Durinck²,

Stawiski³

et al. 2018

Clinical Cancer Research

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“…This may suggest that acquiring resistance to ERK1/2-targeting agents is harder to achieve than acquiring resistance to BRAF or MEK therapy. However, in vitro studies with other ERK1/2 inhibitors have identified specific mutants in ERK1/2 that drive resistance (39,40); these specific mutations have yet to be identified in clinical samples from ERK1/2 inhibitor-relapsed patients.…”

Section: Discussionmentioning

confidence: 99%

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Germann

Furey

Markland

et al. 2017

Molecular Cancer Therapeutics

190

145

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Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to singleagent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway

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Targeting ERK beyond the boundaries of the kinase active site in melanoma

Sammons

Ghose

Tsai

et al. 2019

Molecular Carcinogenesis

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Extracellular signal‐regulated kinase 1/2 (ERK1/2) constitute a point of convergence for complex signaling events that regulate essential cellular processes, including proliferation and survival. As such, dysregulation of the ERK signaling pathway is prevalent in many cancers. In the case of BRAF‐V600E mutant melanoma, ERK inhibition has emerged as a viable clinical approach to abrogate signaling through the ERK pathway, even in cases where MEK and Raf inhibitor treatments fail to induce tumor regression due to resistance mechanisms. Several ERK inhibitors that target the active site of ERK have reached clinical trials, however, many critical ERK interactions occur at other potentially druggable sites on the protein. Here we discuss the role of ERK signaling in cell fate, in driving melanoma, and in resistance mechanisms to current BRAF‐V600E melanoma treatments. We explore targeting ERK via a distinct site of protein‐protein interaction, known as the D‐recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF‐V600E melanoma. Targeting the DRS with inhibitors in melanoma has the potential to not only disrupt the catalytic apparatus of ERK but also its noncatalytic functions, which have significant impacts on spatiotemporal signaling dynamics and cell fate.

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Dissecting Therapeutic Resistance to ERK Inhibition

Cited by 49 publications

References 32 publications

ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Targeting ERK beyond the boundaries of the kinase active site in melanoma

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