P1/2, N=101, Completed, Erasca, Inc. | Active, not recruiting --> Completed

Firstly, although first-generation ATP-competitive inhibitors such as Ulixertinib have shown antitumor activity in early-phase trials, their efficacy varies widely across patient populations and is often accompanied by mechanism-based toxicities (including rash and diarrhea), highlighting a substantial disconnection between preclinical predictions and clinical outcomes...Furthermore, it highlights emerging technological advances, including innovative modalities that address limitations of traditional ATP-competitive inhibitors, such as targeted protein degradation (TPD) approaches. Collectively, this review seeks to outline a clearer roadmap toward realizing the full therapeutic potential of ERK1/2-targeted interventions in cancer treatment.

P1, N=42, Completed, Nader Sanai | Active, not recruiting --> Completed | Trial completion date: Feb 2028 --> Sep 2025

P1/2, N=152, Not yet recruiting, Suzhou Genhouse Bio Co., Ltd.

P2, N=13, Terminated, Dana-Farber Cancer Institute | Active, not recruiting --> Terminated; This was a Simon two stage design trial that terminated after the first stage due to lack of response.

In an HCT116 xenograft model, I-16 (20 mg/kg) elicited significant tumor growth suppression, outperforming Olaparib (50 mg/kg) or BVD-523 (5 mg/kg) monotherapy and achieving efficacy comparable to their combination. These findings suggest that I-16, as the first potent dual PARP1/ERK inhibitor, represents a promising candidate for cancer therapy.

P1, N=40, Recruiting, M.D. Anderson Cancer Center | N=20 --> 40

P1, N=20, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Sep 2025 --> Sep 2027

P1/2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2028 | Trial primary completion date: Dec 2025 --> Dec 2028

P1/2, N=67, Active, not recruiting, D3 Bio (Wuxi) Co., Ltd | Phase classification: P1 --> P1/2 | Trial completion date: Nov 2025 --> Apr 2028 | Trial primary completion date: Nov 2025 --> Apr 2028

Here, we investigated the role of SCAMP3 in ERK1/2 signaling and therapeutic response using TMT-based LC-MS/MS phosphoproteomics of wild-type (WT) and SCAMP3 knockout (SC3KO) SUM-149 cells under basal conditions, after epidermal growth factor (EGF) stimulation, and during ERK1/2 inhibition with MK-8353...These findings position SCAMP3 as a central coordinator of ERK signaling and autophagy. Our results support SCAMP3 as a potential therapeutic target to enhance ERK1/2 inhibitor clinical efficacy and overcome adaptive resistance mechanisms in TNBC.

Our findings establish RAD21-mediated epigenetic regulation as a novel mechanism driving LUAD progression. The efficacy of ulixertinib in suppressing cancer metastasis in preclinical models highlights its translational potential for LUAD therapy.