Our study comprehensively analyzed metabolic gene expression and highlighted the importance of NOX4 in promoting CRC metastasis, suggesting that trametinib could be a potential therapeutic drugs of CRC clinical therapy targeting NOX4.

P1/2, N=16, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | N=31 --> 16 | Trial completion date: Nov 2024 --> Jan 2027 | Trial primary completion date: Nov 2022 --> Jan 2025

P2, N=49, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | N=71 --> 49 | Trial completion date: Jan 2025 --> Apr 2024 | Trial primary completion date: Jan 2025 --> Apr 2024

We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

P1, N=79, Suspended, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. | Phase classification: P1a/1b --> P1 | N=37 --> 79 | Trial completion date: Mar 2023 --> Apr 2024 | Recruiting --> Suspended | Trial primary completion date: Sep 2022 --> Apr 2023

Obtaining tissue for diagnosis can be challenging in this organ. Treatment is challenging when the mass cannot be extracted completely, like in our case, because other forms of therapies are not well studied and warrant further investigation, such as cobimetinib, which is a MEK pathway inhibitor approved in 2022 by the US Food and Drug Administration for histiocytic neoplasms.

These findings suggest that iron-independent lipid peroxidation due to GPx4 disruption induced cell death via the activation of MEK1/ERK2 as a downstream signal of lipid peroxidation in Tamoxifen-treated ETK1 cells. This indicates that GPx4 gene disruption induces slow cell death and involves a different pathway from RSL3- and erastin-induced ferroptosis in ETK1 cells.

Systemic loss of CD36 leaded to the advancement of NAFLD to HCC by causing lipid disorders and metabolic inflammation, a process that involves the activation of MAPK signaling pathway. We found that CD36 contributes significantly to the maintenance of metabolic homeostasis in NAFLD-HCC.

Tunlametinib showed promising antitumor activity with a manageable safety profile in patients with advanced NRAS-mutant melanoma, including those who had prior exposure to immunotherapy. The findings warrant further validation in a randomized clinical trial.

Using this approach, the overall stoichiometry and distribution of 0-4 phosphorylations on MEK1 was determined in a cellular model of drug-resistant metastatic melanoma. This approach can be generalized to other multiply modified proteoforms, for which PTM combinations are key to their function and drug action.

P2, N=86, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Feb 2024

In conclusion, we identified the correlation and effect of STAT1, miR-99b, and MAP2K1 in ALD mouse model and hepatocyte. STAT1, miR-99b, and MAP2K1 may serve as potential therapeutic target of ALD.

P3, N=162, Recruiting, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd. | Not yet recruiting --> Recruiting

Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting...Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.

No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + TCM cell expansion associated with favorable pathologic responses (exploratory outcome).

Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

P1, N=65, Active, not recruiting, Genentech, Inc. | Recruiting --> Active, not recruiting | N=128 --> 65

After initial surgery with subtotal resection, the patient demonstrated durable response to targeted BRAF and MEK inhibitor therapy with vemurafenib and cobimetinib. Our report suggests that targeted therapy may reduce the need for radiation and impact surgical interventions in select cases.

P2, N=80, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Dauricine may be a promising FLT4 inhibitor for the treatment of NSCLC.

P2, N=60, Recruiting, Recursion Pharmaceuticals Inc. | Not yet recruiting --> Recruiting

Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

P2, N=64, Active, not recruiting, University of Sydney | Recruiting --> Active, not recruiting

P2, N=36, Recruiting, Alliance for Clinical Trials in Oncology | Trial primary completion date: Oct 2023 --> Oct 2024

P2, N=17, Recruiting, University of Arkansas | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P2, N=60, Not yet recruiting, Recursion Pharmaceuticals Inc. | Initiation date: Oct 2023 --> Jan 2024

P1/2, N=73, Recruiting, Recursion Pharmaceuticals Inc. | Phase classification: P2 --> P1/2 | N=37 --> 73

P2, N=86, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Feb 2024 --> Dec 2024

P1, N=26, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute

Our findings suggest that while MAPK1 expression, might be a promising biomarker for evaluating oncogenic activity in patients suspected of BCa. We were not able to detect a prognostic/diagnostic role for MAPK1 promoter methylation.

No abstract available

P1/2, N=210, Recruiting, Immuneering Corporation | N=156 --> 210

A significant ex vivo inhibition of proliferation with the combination of roflumilast+cobimetinib was observed compared to dimethyl sulfoxyde control in both models (51 and 67%). To decipher molecular mechanisms underlying this effect, we performed transcriptomic analyses and revealed a decrease in MKI67, RAF1 and CCND1 expression under bitherapy. Our findings strengthen the therapeutic interest of PDE4 inhibitors and support further experiments to evaluate this approach in metastatic melanoma.

P2, N=71, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2024 --> Jan 2025 | Trial primary completion date: Jan 2024 --> Jan 2025

This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease.

Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

P1, N=15, Recruiting, City of Hope Medical Center | Phase classification: P1b --> P1 | Trial completion date: Mar 2024 --> May 2025 | Trial primary completion date: Mar 2024 --> May 2025

Together, these data demonstrate a novel role for MEK1/2 signalling during testis development that is essential for male germline differentiation, but indicate a more limited role for FGF signalling. Our data indicate that additional ligands are likely to act through MEK1/2 to promote male germline differentiation and highlight a need for further mechanistic understanding of male germline development.

Immune cells from pmel-1 mice were isolated, activated with gp100, and cultured in vitro with 100 IU/mL IL-2 and single, dual, or triple therapy with CD27Ag, cobimetinib (MEKi) and/or αPD-L1... CD27 agonism prevents the impairment of T cell activation that was mediated by MEKi. Moreover, this CD27Ag/MEKi/PDL1i triple therapy bolstered trafficking of T cells with stem-like, effector, or resident memory properties, in turn enhancing the antitumor response. This therapy is being evaluated in metastatic CCA patients in an ongoing Phase II clinical trial.

P1, N=42, Recruiting, National Cancer Institute (NCI) | Initiation date: Feb 2024 --> Sep 2023

P1, N=128, Recruiting, Genentech, Inc. | Trial completion date: Sep 2024 --> Nov 2025 | Trial primary completion date: Nov 2023 --> Nov 2025

MEK inhibitors block RAS-ERK pathways in platinum resistant HGSOC cells and PDOs. MEK inhibitors with carboplatin have select synergistic effects which may indicate a strategy to improve platinum sensitivity.