Novel ATP-Competitive MEK Inhibitor E6201 Is Effective against Vemurafenib-Resistant Melanoma Harboring the MEK1-C121S Mutation in a Preclinical Model

Narita, Yusuke; Okamoto, Kiyoshi; Kawada, Megumi Ikemori; Takase, Kazuma; Minoshima, Yukinori; Kodama, Kotaro; Iwata, Masao; Miyamoto, Naokazu; Sawada, Kohei

doi:10.1158/1535-7163.mct-13-0667

Cited by 26 publications

(22 citation statements)

References 37 publications

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“…Interestingly, we found that the MEK mutations we studied provided additional resistance to both MEK and ERK inhibitors in a manner clearly related to their ability to activate ERK since the effect was more pronounced for ERK inhibition than it was for MEK inhibition. This dichotomy suggests that some MEK mutants are not, as has been widely reported (11,30,39) providing direct resistance to the MEK inhibitor; instead, it is the increased level of ERK activation they provide that requires additional inhibition. The increased resistance to ERK inhibition by MEK mutants we report is highly novel and has not been previously reported.…”

Section: Discussionmentioning

confidence: 95%

Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma

et al. 2017

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The development of targeted inhibitors vemurafenib and dabrafenib has led to improved clinical outcome for melanoma patients with BRAFV600E mutations. Although the initial response to these inhibitors can be dramatic, sometimes causing complete tumor regression, the majority of melanomas eventually become resistant. MEK mutations are found in primary melanomas and frequently reported in BRAF melanomas that develop resistance to targeted therapy; however, melanoma is a molecularly heterogeneous cancer, and it remains to be determined which mutations are drivers and which are passengers. In this study, we demonstrate that in BRAFV600E melanoma cell lines, activating MEK mutations drive resistance and contribute to suboptimal growth of the melanoma cells following the withdrawal of BRAF inhibition. In this manner the cells are drug-addicted, suggesting melanoma cells evolve a ‘just right’ level of mitogen-activated protein kinase (MAPK) signaling and the additive effects of MEK and BRAF mutation are counterproductive. We also used a novel mouse model of melanoma to demonstrate that several of these MEK mutants promote the development, growth, and maintenance of melanoma in vivo in the context of Cdkn2a and Pten loss. By utilizing a genetic approach to control mutant MEK expression in vivo we were able to induce tumor regression and significantly increase survival; however, after a long latency, all tumors subsequently became resistant. These data suggest that resistance to BRAF or MEK inhibitors is probably inevitable, and novel therapeutic approaches are needed to target dormant tumors.

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Section: Discussionmentioning

confidence: 95%

Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma

et al. 2017

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“…The rationale of these approaches is to prevent or overcome MAPK inhibitor dependent resistance mechanisms, although the appearance of systemic toxicities remains one of the main concerns when combining several small molecules (115)(116)(117)(118)(119). 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).…”

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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“…E6201 shows identical affinity and residence time for the active and inactive forms of MEK1 (12), and demonstrates different pharmacologic activities than those of allosteric MEK inhibitors and exerts exclusive effects on targeting acquired MEK1-C121S mutation, which confers resistance to the allosteric MEK inhibitor selumetinib (AZD6244) in melanoma (13). E6201 also has a long occupancy time for FLT3 (11-fold longer than that for MEK).…”

Section: Introductionmentioning

confidence: 99%

The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations

et al. 2016

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FLT3 inhibition has elicited encouraging responses in acute myeloid leukemia (AML) therapy. Unfortunately, unless combined with a bone marrow transplant, disease relapse is frequent. In addition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persistently activated in AML cells even when FLT3 phosphorylation is continually suppressed. Thus, concomitant targeting of FLT3 and MAPK may potentially exert synergistic activity to counteract the resistance of AML cells to FLT3-targeted therapy. In this study, we investigated the anti-leukemia activity of a MEK1 and FLT3 dual inhibitor, E6201, in AML cells resistant to FLT3 inhibition. We found that E6201 exerted profound apoptogenic effects on AML cells harboring resistance-conferring FLT3 mutations. This activity appeared to be p53 dependent, and E6201-induced cytotoxicity was retained under hypoxic culture conditions and during co-culture with mesenchymal stem cells that mimic the AML microenvironment. Furthermore, E6201 markedly reduced leukemia burden and improved the survival of mice in a human FLT3-mutated AML model. Collectively, our data provide a preclinical basis for the clinical evaluation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FLT3-targeted monotherapy.

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Novel ATP-Competitive MEK Inhibitor E6201 Is Effective against Vemurafenib-Resistant Melanoma Harboring the MEK1-C121S Mutation in a Preclinical Model

Cited by 26 publications

References 37 publications

Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma

Activated MEK cooperates with Cdkn2a and Pten loss to promote the development and maintenance of melanoma

Overcoming resistance to BRAF inhibitors

The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations

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