Searching for the Chokehold of NRAS Mutant Melanoma

Posch, Christian; Vujic, Igor; Itzinger-Monshi, Babak; Sanlorenzo, Martina; Weihsengruber, Felix; Rappersberger, Klemens; Ortiz‐Urda, Susana

doi:10.1016/j.jid.2016.03.006

Cited by 15 publications

(21 citation statements)

References 73 publications

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“…We observed that targeting mutant NRAS caused significant tumor regression, demonstrating that continuous NRAS signaling is required fortumor maintenance and progression while implicating the inhibition of mutant NRAS as a therapeutic target. Despite decades of research, specific pharmacological inhibition of NRAS has been unsuccessful to date, and efforts to extinguish oncogenic NRAS signaling continue [8]. Genetic suppression of NRAS Q61R in our model was not sufficient to prevent tumor recurrence as resistant tumors developed after a long latency in the absence of mutant NRAS.…”

Section: Discussionmentioning

confidence: 93%

“…Attention has now turned to other genetic subgroups of melanoma, with clinical trials showing the potential utility of targeting the MEK/ERK signaling pathway in NRAS mutant melanoma [8,9,29]. Despite initially encouraging results, the duration of response to MEK inhibitors in this setting is limited, with treatment failure being rapid and resistance being near universal.…”

Section: Discussionmentioning

confidence: 99%

“…In melanoma, this phenomenon has been best studied in the context of mutant BRAF , where signaling from RTKs provides important parallel signals that allow BRAF inhibition to be circumvented [30,31]. Although this adaptive signaling has been little explored in NRAS mutant melanoma, an extensive understanding of these cellular processes will likely prove critical for the development of effective combination therapy strategies [8,29,32]. …”

Section: Discussionmentioning

confidence: 99%

“…NRAS is mutated in 15–20% of melanomas but efforts to pharmacologically inhibit mutant RAS directly have been unsuccessful to date [8]. RAS signals to several downstream effectors including phosphatidyl-inositol-3-kinase (PI3K)/AKT, RAL, and the RAF serine/threonine protein kinases, which activate MEK and extracellular signal–regulated kinase (ERK).…”

Section: Introductionmentioning

confidence: 99%

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Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

et al. 2017

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Targeted therapies have revolutionized cancer care but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice but 40% of tumors recurred. Analysis of resistant tumors revealed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells revealed enhanced efficacy of cytotoxicity with combined RTK and MEK inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

et al. 2017

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“…Other attempts to target mutant NRAS are summarized elsewhere in detail, but, to date, have not shown clear success in vivo [17]. Hence, indirect targeting of NRAS signaling via inhibition of molecules further downstream in the MAPK pathway, such as MEK or ERK has evolved as an alternative strategy to combat NRAS-mutant melanoma.…”

Section: Drug Evaluation Koelblinger Dornbierer and Dummermentioning

confidence: 99%

A review of binimetinib for the treatment of mutant cutaneous melanoma

2017

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UTUREAlthough significant progress has been made in the treatment of unresectable or metastatic melanoma, at least half of all advanced melanoma patients eventually progress and pass away due to their disease. Especially patients with NRAS-mutated melanoma still face limited therapeutic options, with immunotherapy being the current treatment type of choice. Binimetinib is a selective inhibitor of MEK, a central kinase in the tumor-promoting MAPK pathway. The results of a recent Phase III trial rendered binimetinib the first targeted therapy agent to significantly improve progression-free survival in NRAS-mutated melanoma. This review will summarize the development and clinical data of binimetinib in melanoma in general and also explore the potential future role of this substance as single agent or combination therapy. Recently, the advent of targeted therapies and immunotherapy in metastatic melanoma has significantly changed the therapeutic landscape of this devastating disease with impressive tumor responses seen after kinase inhibitor treatment along with a small proportion of patients even achieving long-term survival of 10 years or more after immunotherapy with CTLA-4 antibodies [1][2][3][4][5][6][7]. Despite the availability and effectiveness of these novel treatments, the majority of patients with advanced melanoma still eventually face fatal progression of their disease, thus maintaining an unmet need for the development of further therapeutic agents.While immunotherapy with anti-CTLA-4 or anti-PD1-antibodies in melanoma utilizes a rather universal approach harnessing the patients' own immune system, in other words, T cells to attack and kill aberrant melanocytic tumor cells, targeted therapies, such as BRAF-or MEK-inhibitors aim to reverse the effects of distinct oncogenic mutations that confer proliferation and survival of melanoma cells. Increasing insight into the mutational landscape of cutaneous melanoma by large-scale genomic studies -published by The Cancer Genome Atlas Network and others -has led to the definition of four distinct mutational profiles based on genetic alterations impacting the MAPK pathway in cutaneous melanoma [8,9]. Being the most frequent, BRAF-mutations (predominantly the V600E hotspot mutation) occur in 40-50% of all melanomas, while NRAS-and NF1 mutations are less common, found in approximately 20 and 15% of melanomas, respectively [8][9][10][11]. Of note, BRAF and NRAS mutations are considered to be mutually exclusive despite the recent demonstration of their co-occurrence in melanoma cells, whereas loss-of-function mutations in the tumor suppressor gene NF1 can infrequently be detected both in BRAF-and NRAS-mutated melanomas, albeit being most common in BRAF Wt /NRAS Wt tumors [9,12]. Last, melanomas belonging to the so-called triple

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Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Searching for the Chokehold of NRAS Mutant Melanoma

Cited by 15 publications

References 73 publications

Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

Resistance mechanisms to genetic suppression of mutant NRAS in melanoma

A review of binimetinib for the treatment of mutant cutaneous melanoma

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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