MEK inhibitor resistance mechanisms and recent developments in combination trials

Kun, Eucharist; Tsang, Yvonne T.M.; Ng, Charles Wang Wai; Gershenson, David M.; Wong, Kwong-Kwok

doi:10.1016/j.ctrv.2020.102137

Cited by 108 publications

(70 citation statements)

References 125 publications

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“…The clinical application of MEK inhibitors provides remarkable benefits in advanced and unresectable melanoma patients with concomitant BRAF inhibitor treatment [ 26 , 27 ]. A series of MEK1/2 inhibitors, trametinib, binimetinib, selumetinib, and cobimetinib, have been tested clinically against various type of cancer, but no outcomes have been published to date [ 28 ]. NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) is an ongoing phase II study that individualizes treatment by using targeted drugs, including MEK inhibitors, as pediatric precision medicine based on specific mutation status [ 29 ].…”

Section: Putting the “Brakes” On The Cell Cyclementioning

confidence: 99%

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ando

Nakagawara

2021

Biomolecules

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Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

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Section: Putting the “Brakes” On The Cell Cyclementioning

confidence: 99%

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Ando

Nakagawara

2021

Biomolecules

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“…Alternatively, in some patients, the PI3K/AKT pathway, a secondary signaling route becomes hyper-activated [ 19 ]. Adaptive resistance to MEKi likewise is acquired by reactivation of MAPK signaling (e.g., ERK) or activation of parallel signaling pathways (e.g., PI3K, STAT and Hippo signaling pathways) [ 20 ]. Yet, a considerable proportion of BRAFi resistant tumors (40%) displays mechanisms of resistance that have not been fully revealed [ 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

BRAF/EZH2 Signaling Represses miR-129-5p Inhibition of SOX4 Thereby Modulating BRAFi Resistance in Melanoma

Gebhardt

Edemir

Groß

et al. 2021

Cancers

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Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma.

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“…Since MEK is rarely mutated in human cancer, it was not considered an effective target in the past, but with increasing knowledge of the role of the MAPK/ERK signaling in cancer, targeting MEK is attracting more and more attention [ 140 ]. Among the MEK inhibitors, selumetinib, recently approved by the FDA, was effective in patients with relapsed low-grade serous ovarian cancer (LGSOC) in a phase II clinical trial and patients with neurofibromatosis type 1 [ 141 , 142 , 143 ]. Another MEK inhibitor, trametinib, showed an improvement in PFS compared with the current standard of care in patients with recurrent LGSOC [ 144 ].…”

Section: Mapk/erk Signaling Pathway In Hccmentioning

confidence: 99%

“…Several mechanisms have been proposed for the reactivation of the signaling in cancer following treatment with MEK inhibitors. Reactivation can occur through alterations or mutations to upstream molecules such as RTKs, RAS, RAF, or NF1, reinforcing the signaling pathway [ 141 , 156 ]. Resistance to MEK inhibitors can also occur when a mutation has arisen in MEK, leading to impaired drug binding to MEK [ 141 ].…”

Section: Mapk/erk Signaling Pathway In Hccmentioning

confidence: 99%

“…Apart from reactivation of the MAPK/ERK signaling pathway, cancers acquire resistance to MAPK/ERK signaling-based target therapy by recruiting an alternative signaling pathway that induces cell proliferation and growth. In particular, activation of the PI3K/AKT and yes-associated protein (YAP) signaling pathways stand out as the bypass mechanisms for resistance to therapeutic interventions of the MAPK/ERK signaling [ 141 ]. For example, colorectal cancer cells with an activating mutation in K-RAS became resistant to the inhibition of EGFR and MEK via activation of PI3K/AKT [ 157 ].…”

Section: Mapk/erk Signaling Pathway In Hccmentioning

confidence: 99%

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MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

Moon

2021

Cancers

153

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Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.

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MEK inhibitor resistance mechanisms and recent developments in combination trials

Cited by 108 publications

References 125 publications

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

BRAF/EZH2 Signaling Represses miR-129-5p Inhibition of SOX4 Thereby Modulating BRAFi Resistance in Melanoma

MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

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