Current Development Status of MEK Inhibitors

Cheng, Ying; Tian, Hongqi

doi:10.3390/molecules22101551

Cited by 202 publications

(143 citation statements)

References 97 publications

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“…In melanoma, combination BRAF and MEK inhibitors with an A2AR antagonist induces significant tumor control in preclinical studies (41). MEK is a promising target for KRAS, NRAS, and BRAF mutant tumors and is being targeted in CRC (260). Recently, MEK inhibitor, cobimetinib, combined with anti-PD-L1 therapy (atezolizumab) failed to improve survival in microsatellite-stable metastatic CRC patients in a phase 3 clinical trial (261).…”

Section: Discussionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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CD73, a cell surface 5 ′ nucleotidase that generates adenosine, has emerged as an attractive therapeutic target for reprogramming cancer cells and the tumor microenvironment to dampen antitumor immune cell evasion. Decades of studies have paved the way for these findings, starting with the discovery of adenosine signaling, particularly adenosine A2A receptor (A2AR) signaling, as a potent suppressor of tissue-devastating immune cell responses, and evolving with studies focusing on CD73 in breast cancer, melanoma, and non-small cell lung cancer. Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. Evidence is mounting that shows promise for improving patient outcomes through incorporation of immunomodulatory strategies as single agents or in combination with current treatment options. Recently, several immune checkpoint inhibitors received FDA approval for use in GI cancers; however, clinical benefit is limited. Investigating molecular mechanisms promoting immunosuppression, such as CD73, in GI cancers can aid in current efforts to extend the efficacy of immunotherapy to more patients. In this review, we discuss current clinical and basic research studies on CD73 in GI cancers, including gastric, liver, pancreatic, and colorectal cancer, with special focus on the potential of CD73 as an immunotherapy target in these cancers. We also present a summary of current clinical studies targeting CD73 and/or A2AR and combination of these therapies with immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

et al. 2020

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“…58 Two MEK inhibitors, trametinib and cobimetinib, 59,60 are currently approved for the treatment of melanoma and more than 10 other MEK1/2 inhibitors are in various stages of clinical testing across a spectrum of cancer types including breast cancer. 61 In addition to its cell-intrinsic protumorigenic effects, MAPK signaling has also been implicated in the upregulation of checkpoint ligands such as PD-L1. 62,63 Therefore, combination of immunotherapy with MEK1/2 inhibitors has great potential to block both tumor-intrinsic and immune-mediated protumorigenic effects of the MAPK signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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“…Two MEK inhibitors (trametinib and cobimetinib) have been developed and approved for treating BRAF(V600E)-harboring cancers as single agents or together with RAF inhibitors, while ERK inhibitors are still undergoing clinical trials. In contrast to RAF inhibitors, these inhibitors have no paradoxical effect, but they do have a lower therapeutic index since they strongly inhibit this signaling pathway in normal cells [321,322]. This also implies that targeting downstream MEK/ERK may not be a good choice to treat Ras-or RAF-mutated cancers.…”

Section: Raf/mek/erk Inhibitors and Resistancementioning

confidence: 99%

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Degirmenci

Wang

2020

Cells

399

303

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The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

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Current Development Status of MEK Inhibitors

Cited by 202 publications

References 97 publications

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

CD73's Potential as an Immunotherapy Target in Gastrointestinal Cancers

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

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