temuterkib (LY3214996)

Vertical inhibition of the RAS/MEK/ERK pathway by targeting SHP2 or SOS1 and the downstream kinases MEK (trametinib) or ERK (temuterkib) was highly effective. Inhibition of upstream tyrosine receptor kinases with nintedanib in combination with batoprotafib or BI-3406 was also effective, and in combination with sotorasib, demonstrated synergy in spheroids harboring KRAS G12C. Dual inhibition of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways by batoprotafib or sotorasib with either the mTORC1/2 inhibitor sapanisertib or the AKT inhibitor ipatasertib demonstrated combination activity, primarily in spheroids harboring KRAS G12C. The BCL-2 inhibitor venetoclax in combination with sotorasib, batoprotafib or BI-3406 resulted in additive and synergistic cytotoxicity. Lastly, concurrent inhibition of the KRAS pathway with sotorasib and batoprotafib demonstrated combination activity in spheroids containing KRAS G12C.

P1, N=17, Completed, Dana-Farber Cancer Institute | Recruiting --> Completed | N=42 --> 17

Moreover, the MAPK signaling pathway inhibitor LY3214996 suppressed these effects. Taken together, our findings suggest that low-intensity focused ultrasound enhances angiogenesis and neurogenesis and improves neurological function following traumatic brain injury by regulating the expression of Orexin-A/Orexin-A receptor 1, which activates the MAPK signaling pathway.

Upregulation of ACTN1 by FBXO25 promotes the progression of ovarian cancer by activating the ERK1/2 signaling pathway and M2 polarization of macrophages. The FBXO25/ACTN1/ERK1/2 axis and M2 macrophages may represent promising targets for developing ovarian cancer treatments.

P1, N=50, Active, not recruiting, Nader Sanai | Recruiting --> Active, not recruiting | Trial completion date: Feb 2025 --> Feb 2028

P1, N=24, Terminated, The Netherlands Cancer Institute | N=55 --> 24 | Recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Jul 2024; Due to a lack of safety and efficacy.

This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening.

ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations.

P1/2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=42, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Apr 2024 --> Apr 2025

Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.

P1, N=50, Recruiting, Nader Sanai | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Dec 2024