Co‐targeting
            <scp>BET</scp>
            and
            <scp>MEK</scp>
            as salvage therapy for
            <scp>MAPK</scp>
            and checkpoint inhibitor‐resistant melanoma

Echevarría-Vargas, Ileabett M.; Reyes-Uribe, Patricia; Guterres, Adam N.; Yin, Xiangfan; Kossenkov, Andrew V.; Liu, Qin; Zhang, Gao; Krepler, Clemens; Cheng, Chaoran; Wei, Zhi; Somasundaram, Rajasekharan; Karakousis, Giorgos C.; Xu, Wei; Morrissette, Jennifer J.D.; Lu, Yiling; Mills, Gordon B.; Sullivan, Ryan J.; Miao, Benchun; Frederick, Dennie T.; Boland, Genevieve M.; Flaherty, Keith T.; Weeraratna, Ashani T.; Herlyn, Meenhard; Amaravadi, Ravi K.; Schuchter, Lynn M.; Burd, Christin E.; Aplin, Andrew E.; Xu, Xiaowei; Villanueva, Jessie

doi:10.15252/emmm.201708446

Cited by 84 publications

(76 citation statements)

References 58 publications

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“…MEK/BET combination inhibition can suppress MAPK and checkpoint inhibitor resistant melanoma in animal models including those exhibiting NRAS mutations (27). Although BET and MEK inhibitors would be expected to have effects on normal lymphocytes as well, the combination had activity also in immune competent mice and did not impair immune cells.…”

Section: Discussionmentioning

confidence: 99%

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

Funck‐Brentano

Vizlin‐Hodzic

Nilsson

et al. 2020

Preprint

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1) Background: BET bromodomain proteins regulate transcription by binding acetylated 8 histones and attracting key factors for e.g. transcriptional elongation. BET inhibitors have been 9 developed to block pathogenic processes such as cancer and inflammation. Despite having potent 10 biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating 11 cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this 12 in glioma has been made. (2) Methods: Here, we have conducted a pharmacological synergy screen 13 in glioma cells to search for possible combination treatments augmenting the apoptotic response to 14 BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy 15 four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. 16Data was also generated using other BET inhibitors. (3) Results: In the synergy screen, we 17 discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and 18 human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA 19 but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors. (4) 20 Conclusions: Our findings validate a combination therapy previously demonstrated to exhibit anti-21 cancer activities in multiple other tumor types but which appears to have been lost in translation to 22 the clinic.23 Keywords: BET bromodomain protein, hexamethylene bisacetamide, glioma 24 25 1. Introduction 26 Before the discovery of oncogenes the concept of cancer cell differentiation therapy was explored 27 therapeutically, in part based on early observations that dimethylsulfoxide (DMSO) can cause 28 differentiation of Friend virus induced mouse erythroleukemia (MEL) cells into hemoglobin 29producing red blood cells (1). Efforts to produce more potent cancer differentiation compounds 30 generated two molecules that were tested in the clinic, hexamethylene bisacetamide (HMBA) and 31 suberoylanilide hydroxamic acid (SAHA, later renamed to vorinostat) (2, 3). Whereas SAHA was 32 found to inhibit histone deacetylases (HDACs) 1-3 and made it to clinical approval for cutaneous T-33 cell leukemia, HMBA neither inhibits HDACs nor received clinical approval, and its target was 34 unknown for forty years (4, 5). Recently, however, we discovered that HMBA is a bromodomain and 35 extra-terminal domain (BET) inhibitor, with highest binding affinity for bromodomain 2 (BD2) of BET 36 proteins BRD2, BRD3 and BRD4 while also inhibiting the bromodomain of histone acetyltransferase 37 P300 (6). The structure of HMBA largely resembles that of an acetylated lysine, explaining the mode 38 of action. 40Although HMBA was likely the first anti-cancer compound used in the clinic that inhibited BET 41 bromodomain proteins, the concept of BET inhibitors (BETis) were largely popularized with the 42 development of the low nanomolar BETis JQ1 and iBET-151 (7, 8). The mechanism of action of thes...

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Section: Discussionmentioning

confidence: 99%

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

Funck‐Brentano

Vizlin‐Hodzic

Nilsson

et al. 2020

Preprint

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“…However, the combination of BETi/MEKi was able to induce robust antitumor effects in NRAS‐mutant melanoma. Considering that the MEK inhibitor trametinib 41 is an FDA‐approved drug for BRAF‐mutant melanoma patients, and different BETi such as OTX‐015 29 are in advanced clinical trials, clinical studies based on the combination of trametinib 41 and OTX‐015 29 (Combination G, Figure ) could be rapidly implemented for therapy‐resistant melanoma …”

Section: The Mmt Approachmentioning

confidence: 99%

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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“…MEK inhibitors are also associated with primary and acquired resistance as well as frequent toxicity-related adverse events (14,15). However, MEK inhibitors could deliver promising therapies when combined with inhibitors of other signaling mechanisms (12,(15)(16)(17). Currently, the MEK inhibitor FCN-159, which has 10-fold higher selectivity against activated MEK1/2 compared to trametinib, is being investigated as a single agent in a phase I clinical trial (NCT03932253).…”

Section: Introductionmentioning

confidence: 99%

“…Considering the lack of success of therapies targeting BRAF and MEK in NRAS mutant melanoma patients (42), recent efforts have been focused on finding other therapeutic targets and development of combination therapies. For example, inhibiting a novel NRAS-activating kinase (STK19) and combining MEK inhibitors with inhibitors of the MER receptor tyrosine kinase (MERTK), BET, and HDAC have been reported to block NRAS mutant melanoma growth in vitro and in vivo(15)(16)(17)43). In this study, we demonstrate that the combination of aRho/MRTF pathway inhibitor, CCG-222740 and the MEK inhibitor trametinib synergistically inhibited viability of a subset of NRAS mutant melanoma cells and also induced apoptosis in cell with highly activated Rho/MRTF pathway.…”

mentioning

confidence: 99%

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

Appleton

Palsuledesai

Misek

et al. 2019

Preprint

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The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (~50% BRAF V600 mutations and ~30% NRAS mutations). While targeted therapies have yielded success in BRAF V600 mutant melanoma patients, such therapies have been ineffective in NRAS mutant melanomas in part due to their cytostatic effects and primary resistance in this patient population. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. Combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells which have a high level of trametinib resistance. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlights the potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

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Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma

Cited by 84 publications

References 58 publications

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

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