Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms

Johnson, Douglas B.; Menzies, Alexander M.; Zimmer, Lisa; Eroglu, Zeynep; Ye, Fei; Zhao, Shilin; Rizos, Helen; Sucker, Antje; Scolyer, Richard A.; Gutzmer, Ralf; Gogas, Helen; Kefford, Richard; Thompson, John F.; Becker, Jürgen C.; Berking, Carola; Egberts, Friederike; Loquai, Carmen; Goldinger, Simone M.; Pupo, Gulietta M.; Hugo, Willy; Kong, Xiangju; Garraway, Levi A.; Sosman, Jeffrey A.; Ribas, Antoni; Lo, Roger S.; Long, Georgina V.; Schadendorf, Dirk

doi:10.1016/j.ejca.2015.08.022

Cited by 275 publications

(238 citation statements)

References 35 publications

(43 reference statements)

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“…The elucidation of secondary mechanisms of resistance to BRAF-directed therapies has generated a substantial literature 115 , although larger datasets and meta-analyses have revealed that only a handful of changes underlie the preponderance of genomic resistance mechanisms. In the largest studies to date 20,[116][117][118] , involving 132 samples obtained at the time of clinical resistance, one or more genomic causes of resistance were identified in 58% of patients: NRAS/KRAS mutation in 20%, BRAF splice vari ants in 16%, BRAF amplification in 13%, MEK1/2 mutation in 7%, and non-MAPK-pathway alterations in 11%. Similar resistance mechanisms have been described with combined BRAF-MEK inhibition 119,120 .…”

Section: Braf-mek-inhibitor Resistance and Biomarkersmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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Section: Braf-mek-inhibitor Resistance and Biomarkersmentioning

confidence: 99%

Targeted agents and immunotherapies: optimizing outcomes in melanoma

et al. 2017

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“…MEK1/2 mutations, including MEK1 Q56P , have been implicated in both single-agent BRAF and combination BRAF/MEK targeting therapy-acquired resistance in patients (18,21,(34)(35)(36). Single-agent assays demonstrated that relative to the parental BRAF V600E ::MEK1 wt cells, the double-mutant BRAF V600E ::MEK1 Q56P cells displayed a markedly reduced sensitivity to the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib (Fig.…”

Section: Bvd-523 Exhibits Activity In In Vitro Models Of Braf and Mekmentioning

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

178

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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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“…BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6)(7)(8)(9). Despite these findings, ∼15% of BRAF mutant cancers do not respond to BRAF inhibitors, and the majority of patients who achieve a response will inevitably acquire resistance to these targeted agents, predominantly through reactivation of MAPK pathway signaling (4,(10)(11)(12)(13)(14)(15)(16).…”

Section: G466vmentioning

confidence: 92%

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

Okimoto

Olivas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Oncogenic activation of protein kinase BRAF drives tumor growth by promoting mitogen-activated protein kinase (MAPK) pathway signaling. Because oncogenic mutations in BRAF occur in ∼2-7% of lung adenocarcinoma (LA), BRAF-mutant LA is the most frequent cause of BRAF-mutant cancer mortality worldwide. Whereas most tumor types harbor predominantly the BRAF V600E -mutant allele, the spectrum of BRAF mutations in LA includes BRAF V600E (∼60% of cases) and non-V600E mutant alleles (∼40% of cases) such as BRAF G469A and BRAF G466V. The presence of BRAF V600E in LA has prompted clinical trials testing selective BRAF inhibitors such as vemurafenib in BRAF V600E -mutant patients. Despite promising clinical efficacy, both innate and acquired resistance often result from reactivation of MAPK pathway signaling, thus limiting durable responses to the current BRAF inhibitors. Further, the optimal therapeutic strategy to block non-V600E BRAF-mutant LA remains unclear. Here, we report the efficacy of the Raf proto-oncogene serine/ threonine protein kinase (RAF) inhibitor, PLX8394, that evades MAPK pathway reactivation in BRAF-mutant LA models. We show that PLX8394 treatment is effective in both BRAF V600E and certain non-V600 LA models, in vitro and in vivo. PLX8394 was effective against treatment-naive BRAF-mutant LAs and those with acquired vemurafenib resistance caused by an alternatively spliced, truncated BRAF V600E that promotes vemurafenib-insensitive MAPK pathway signaling. We further show that acquired PLX8394 resistance occurs via EGFR-mediated RAS-mTOR signaling and is prevented by upfront combination therapy with PLX8394 and either an EGFR or mTOR inhibitor. Our study provides a biological rationale and potential polytherapy strategy to aid the deployment of PLX8394 in lung cancer patients.ncogenic mutations in the BRAF serine/threonine protein kinase occur in a wide spectrum of solid tumor malignancies, most notably melanoma, colorectal cancer, and lung adenocarcinoma (1). Mutant BRAF promotes tumor growth by hyperactivating the RAF-MEK-ERK signaling cascade (2-5). BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6-9). Despite these findings, ∼15% of BRAF mutant cancers do not respond to BRAF inhibitors, and the majority of patients who achieve a response will inevitably acquire resistance to these targeted agents, predominantly through reactivation of MAPK pathway signaling (4, 10-16).The clinical efficacy of RAF inhibitors depends on the degree of suppression of MAPK pathway output (8). Vemurafenib and dabrafenib paradoxically activate the MAPK pathway in cells with oncogenic RAS or increased upstream receptor signaling, thereby enhancing cellular proliferation that can promote cutaneous squamous cell carcinomas and keratoacanthomas that often harbor RAS mutations, and potentially other RAS-driven malignancies (17-25). Combination therapy with a MEK i...

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Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms

Cited by 275 publications

References 35 publications

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Targeted agents and immunotherapies: optimizing outcomes in melanoma

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

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

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