Selumetinib: a selective MEK1 inhibitor for solid tumor treatment

Hedayat, Mohaddeseh; Jafari, Reza; Zolbanin, Naime Majidi

doi:10.1007/s10238-021-00783-z

Cited by 14 publications

(9 citation statements)

References 94 publications

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“…These data suggest that FTO and YTHDF1 regulate cancer growth through H-Ras. Consequently, we further examined whether FTO and YTHDF1 regulate resistance of cancer cells to selumetinib, a kinase inhibitor targeting H-Ras downstream MEK1/2 ( 42 ). Cell proliferation assay showed that H-Ras KD prevented the acquired resistance to selumetinib by FTO KD, and H-Ras OE reversed the reduction of YTHDF1 KD on the resistance to selumetinib ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Epitranscriptic regulation of HRAS by N ⁶ -methyladenosine drives tumor progression

Pan

Liu

et al. 2023

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

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Overexpression of Ras, in addition to the oncogenic mutations, occurs in various human cancers. However, the mechanisms for epitranscriptic regulation of RAS in tumorigenesis remain unclear. Here, we report that the widespread N 6 -methyladenosine (m 6 A) modification of HRAS , but not KRAS and NRAS , is higher in cancer tissues compared with the adjacent tissues, which results in the increased expression of H-Ras protein, thus promoting cancer cell proliferation and metastasis. Mechanistically, three m 6 A modification sites of HRAS 3′ UTR, which is regulated by FTO and bound by YTHDF1, but not YTHDF2 nor YTHDF3, promote its protein expression by the enhanced translational elongation. In addition, targeting HRAS m 6 A modification decreases cancer proliferation and metastasis. Clinically, up-regulated H-Ras expression correlates with down-regulated FTO and up-regulated YTHDF1 expression in various cancers. Collectively, our study reveals a linking between specific m 6 A modification sites of HRAS and tumor progression, which provides a new strategy to target oncogenic Ras signaling.

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Section: Resultsmentioning

confidence: 99%

Epitranscriptic regulation of HRAS by N ⁶ -methyladenosine drives tumor progression

Pan

Liu

et al. 2023

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

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“…Selumetinib, having a similar structure as binimetinib ( Table 3 ), has been approved in 2020 by the FDA as monotherapy for the treatment of Neurofibromatosis type 1 (NF-1) ( Markham and Keam, 2020 ). It is a more selective and potent second-generation allosteric MEK1/2 inhibitor ( Hedayat et al, 2022 ). Selumetinib is still under investigation for a variety of solid tumors, for example, phase II trials for endometrial cancer and non-small cell lung cancer ( Coleman et al, 2015 ; Seto et al, 2018 ), and a phase III trial in differentiated thyroid ( Ho et al, 2022 ), and melanoma ( Carvajal et al, 2018 ).…”

Section: Inhibitors Targeting Vegfr Downstream Signalingmentioning

confidence: 99%

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Wang,

Liu,

Broussy

et al. 2024

Front. Pharmacol.

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Vascular endothelial growth factors (VEGF), Vascular endothelial growth factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological and pathological angiogenesis. In the last 20 years, many anti-angiogenic drugs have been developed based on VEGF/VEGFR system to treat diverse cancers and retinopathies, and new drugs with improved properties continue to emerge at a fast rate. They consist of different molecular structures and characteristics, which enable them to inhibit the interaction of VEGF/VEGFR, to inhibit the activity of VEGFR tyrosine kinase (TK), or to inhibit VEGFR downstream signaling. In this paper, we reviewed the development of marketed anti-angiogenic drugs involved in the VEGF/VEGFR axis, as well as some important drug candidates in clinical trials. We discuss their mode of action, their clinical benefits, and the current challenges that will need to be addressed by the next-generation of anti-angiogenic drugs. We focus on the molecular structures and characteristics of each drug, including those approved only in China.

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“…This pathway is frequently dysregulated in several cancers, including mCRPC ( Abida et al, 2019 ), although RAS mutations are rare ( Cho et al, 2006 ). Selumetinib is a second-generation, selective, potent, non-ATP-competitive, allosteric MEK1/2 inhibitor that has been tested in different types of tumors at preclinical and clinical levels ( Hedayat et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Dual inhibition of MEK and PI3Kβ/δ–a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer

Ruiz de Porras,

Bernat-Peguera,

Alcon

et al. 2024

Front. Pharmacol.

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Background: Docetaxel remains the standard treatment for metastatic castration-resistant prostate cancer (mCRPC). However, resistance frequently emerges as a result of hyperactivation of the PI3K/AKT and the MEK/ERK pathways. Therefore, the inhibition of these pathways presents a potential therapeutic approach. In this study, we evaluated the efficacy of simultaneous inhibition of the PI3K/AKT and MEK/ERK pathways in docetaxel-resistant mCRPC, both in vitro and in vivo.Methods: Docetaxel-sensitive and docetaxel-resistant mCRPC cells were treated with selumetinib (MEK1/2 inhibitor), AZD8186 (PI3Kβ/δ inhibitor) and capivasertib (pan-AKT inhibitor) alone and in combination. Efficacy and toxicity of selumetinib+AZD8186 were tested in docetaxel-resistant xenograft mice. CRISPR-Cas9 generated a PTEN-knockdown docetaxel-resistant cell model. Changes in phosphorylation of AKT, ERK and downstream targets were analyzed by Western blot. Antiapoptotic adaptations after treatments were detected by dynamic BH3 profiling.Results: PI3K/AKT and MEK/ERK pathways were hyperactivated in PTEN-wild-type (wt) docetaxel-resistant cells. Selumetinib+AZD8186 decreased cell proliferation and increased apoptosis in PTEN-wt docetaxel-resistant cells. This observation was further confirmed in vivo, where docetaxel-resistant xenograft mice treated with selumetinib+AZD8186 exhibited reduced tumor growth without additional toxicity.Conclusion: Our findings on the activity of selumetinib+AZD8186 in PTEN-wt cells and in docetaxel-resistant xenograft mice provide an excellent rationale for a novel therapeutic strategy for PTEN-wt mCRPC patients resistant to docetaxel, in whom, unlike PTEN-loss patients, a clinical benefit of treatment with single-agent PI3K and AKT inhibitors has not been demonstrated. A phase I-II trial of this promising combination is warranted.

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Selumetinib: a selective MEK1 inhibitor for solid tumor treatment

Cited by 14 publications

References 94 publications

Epitranscriptic regulation of HRAS by N ⁶ -methyladenosine drives tumor progression

Epitranscriptic regulation of HRAS by N ⁶ -methyladenosine drives tumor progression

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Dual inhibition of MEK and PI3Kβ/δ–a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer

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Selumetinib: a selective MEK1 inhibitor for solid tumor treatment

Cited by 14 publications

References 94 publications

Epitranscriptic regulation of HRAS by N 6 -methyladenosine drives tumor progression

Epitranscriptic regulation of HRAS by N 6 -methyladenosine drives tumor progression

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Dual inhibition of MEK and PI3Kβ/δ–a potential therapeutic strategy in PTEN-wild-type docetaxel-resistant metastatic prostate cancer

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Product

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Epitranscriptic regulation of HRAS by N ⁶ -methyladenosine drives tumor progression

Epitranscriptic regulation of HRAS by N ⁶ -methyladenosine drives tumor progression