Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

Herrero, Ana; Pinto, Adán; Colón-Bolea, Paula; Casar, Berta; Jones, Martin; Agudo-Ibáñez, Lorena; Vidal, Rebeca; Tenbaum, Stephan P.; Nuciforo, Paolo; Valdizán, Elsa M.; Horváth, Zoltán; Őrfi, László; Pineda‐Lucena, Antonio; Bony, Emilie; Kéri, Gÿorgý; Rivas, Germán; Pazos, Ángel; Gozalbes, Rafael; Pálmer, Héctor G.; Hurlstone, Adam; Crespo, Piero

doi:10.1016/j.ccell.2015.07.001

Cited by 127 publications

(107 citation statements)

References 35 publications

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“…Other groups have attempted to tackle mechanisms of resistance related to the appearance of mutations in MEK1/2 and novel MEK inhibitors active in some of these mutants show interesting potential (120). An avenue of action expected to draw increasing attention is the use of ERK inhibitors (121)(122)(123). Whether in combination with BRAF or MEK inhibitors, small molecule inhibitors such as SCH772984 and GDC-0994 are being tested at present.…”

Section: Potential For Alternative Combination Therapiesmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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Abstract:The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/ MEK inhibitors.

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Section: Potential For Alternative Combination Therapiesmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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“…Recent efforts have demonstrated that pharmacologically targeting ERK dimerization can lead to a significant reduction in RAS-driven tumor growth by potently inhibiting phosphorylation of ERK cytoplasmic substrates. The ERK dimerization inhibitor DEL-22379 reduced tumor growth in mutant KRAS xenograft models and was able to overcome upstream resistance mechanisms, including NRAS overexpression and MEK mutation [87] . Among ERK1/2 cytoplasmic substrates that drive tumorigenesis are the RSK serine/threonine kinases.…”

Section: Erk Substratesmentioning

confidence: 99%

Targeting RAS -mutant Cancers: Is ERK the Key?

et al. 2015

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The three RAS genes comprise the most frequently mutated oncogene family in cancer. With significant and compelling evidence that continued function of mutant RAS is required for tumor maintenance, it is widely accepted that effective anti-RAS therapy will have a significant impact on cancer growth and patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, a clinically effective anti-RAS drug has yet to be developed. With the recent renewed interest in targeting RAS, exciting and promising progress has been made. In this review, we discuss the prospects and challenges of drugging oncogenic RAS. In particular we focus on new inhibitors of RAS effector signaling and the ERK mitogen-activated protein kinase cascade.

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“…ERK is also targeted by matrine (21). The ERK pathway plays an important role in cell proliferation, migration and apoptosis (17). Previous studies reported the relationship between matrine and the ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

“…The ERK signaling pathway plays an important role in cell growth, survival and apoptosis (17). Studies showed that the inhibition of the ERK pathway positively reduced RMS cell growth, survival, and epithelial-mesenchymal transition (EMT) (7)(8)(9).…”

Section: Matrine Inhibited the Proliferation And Induced Apoptosis Ofmentioning

confidence: 99%

Matrine inhibits cell proliferation and induces apoptosis of human rhabdomyosarcoma cells via downregulation of the extracellular signal-regulated kinase pathway

2017

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Abstract. Matrine, extracted from the Chinese traditional medicine Sophorae flavescentis, has been demonstrated to exhibit antitumor effects on numerous types of cancer in vivo and in vitro with low toxicity. However, its antitumor mechanism in rhabdomyosarcoma (RMS) cells remains unclear. In the present study, the antitumor effects of matrine and its underlying mechanisms in RMS were investigated in vitro. The results demonstrated that matrine inhibited cell proliferation, migration and invasion, and induced apoptosis of RMS cells in a dose-dependent manner. Furthermore, the expression levels of phosphorylated mitogen-activated protein kinase (p-MEK) and phosphorylated extracellular signal-regulated kinase (p-ERK) significantly decreased in RMS cells following matrine treatment. In addition, the apoptotic effects of matrine in RMS cells were partially inhibited upon MEK1 overexpression and enhanced upon combined treatment with an ERK inhibitor (U0126). In addition, the ratio of apoptosis regulator BCL-2/BAX significantly decreased following matrine treatment. In conclusion, these findings indicate that matrine inhibits cell proliferation and induces the apoptosis of RMS cells by suppressing the ERK signaling pathway, and may be a novel effective candidate for the treatment of patients with RMS.

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Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes

Cited by 127 publications

References 35 publications

Overcoming resistance to BRAF inhibitors

Overcoming resistance to BRAF inhibitors

Targeting RAS -mutant Cancers: Is ERK the Key?

Matrine inhibits cell proliferation and induces apoptosis of human rhabdomyosarcoma cells via downregulation of the extracellular signal-regulated kinase pathway

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