Combining SDUY104 with an ERK inhibitor Ulixertinib produced synergistic antiproliferative activity via enhanced MAPK suppression. In a PANC-1 xenograft model, combination of SDUY104 with BKM-120 exhibited superior antitumor activity compared to either monotherapy. Collectively, this study identifies a potent SHP2 allosteric inhibitor and delineates a critical compensatory signaling mechanism underlying resistance to SHP2-targeted therapy, providing proof-of-concept support for pancreatic cancer treatment.

Our findings suggest that GDF15 is upregulated in response to ionizing radiation and may participate in epithelial cell senescence during the development of RILI. This process appears to be associated with the ERK1/2-p16 signaling pathway. These results provide additional insight into the molecular mechanisms underlying RILI and suggest that GDF15 may represent a potential target for future therapeutic intervention.

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

Elevated oxidative burden was associated with caspase-3 activation and concentration-dependent suppression of ERK1/2 phosphorylation, both of which were attenuated by N-acetylcysteine (NAC) co-treatment...Notably, NAC co-treatment partly restored p-ERK1/2 levels under the IC50 condition (P<0.01 vs. D-salicin alone), supporting a redox-linked contribution to ERK pathway modulation. Collectively, these findings indicated that D-salicin exerts selective anticancer effects in endometrial cancer cells by inducing oxidative stress and disrupting ERK1/2-mediated survival signaling, with NAC-sensitive modulation consistent with involvement of a redox-responsive ROS-ERK axis.

In vivo, apatinib markedly suppressed xenograft tumor growth and modulated the corresponding signaling pathways. Collectively, our findings identify apatinib as a promising therapeutic agent that disrupts interconnected survival and angiogenic networks in SS.

By synergistically activating ULK1 and inhibiting ERK1/2, UE01 could disrupt the functional coupling of Exo70/Cav-1, thereby inhibiting the secretion of MMP-2/MMP-9 and extracellular matrix degradation. Taken together, these results demonstrate that a dual-target strategy against ERK1/2 attenuates TNBC growth and metastatic dissemination by disrupting the Exo70/Cav-1/MMPs axis, highlighting UE01 as a potential lead compound for future targeted therapy.

This led to growth inhibition and apoptosis of K562-tumor xenograft. These results indicate that TQ enhances CML cells' apoptosis by hypomethylating and re-expressing SOCS-3, inhibiting ERK1/2 and modulating the apoptosis-regulator gene expression and by showing consistent interaction with most of anti-apoptotic proteins, enhancing its potential as a scaffold for designing novel inhibitors to combat CML cells.

P1/2, N=36, Active, not recruiting, Ipsen | Recruiting --> Active, not recruiting | N=220 --> 36

Sufficient exposure to RMC-4630 and LY3214996 was not reached due to the toxicity profile of the combination. Tumor response was not demonstrated at the explored dose levels. Therefore, the dose escalation was discontinued, and the RP2D was not determined.

P2, N=20, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027

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.