The lack of clinical efficacy may be due to inadequate inhibition of RAS-to-ERK signaling as toxicities necessitated dose reduction. NCT05068752.

P1, N=86, Active, not recruiting, Erasca, Inc. | Trial completion date: Nov 2025 --> Dec 2026

P3, N=78, Active, not recruiting, Erasca, Inc. | Recruiting --> Active, not recruiting | N=470 --> 78

P2/3, N=30, Not yet recruiting, Cancer Research UK

Collectively, these findings demonstrate that ONC disrupts redox homeostasis, mitochondrial function, and survival signaling in melanoma cells, exerting particularly potent effects in BRAF inhibitor-resistant populations. This study provides mechanistic insight into the anti-melanoma activity of ONC and supports its potential therapeutic application in drug-resistant melanoma.

Therefore, this study aimed to examine the protein composition of the secretome of cells resistant to vemurafenib (a BRAF inhibitor) and cobimetinib (a MEK inhibitor) and to compare it with that of nonresistant cells. Proteins secreted by resistant melanoma cells can undoubtedly influence the surrounding microenvironment in a way that promotes the formation of a pro-tumor niche. Among the proteins secreted in significantly higher amounts by resistant cells (compared to the control group), which may be potential biomarkers or therapeutic targets in melanoma, plasminogen activator inhibitor 1, thymosin beta-4, clusterin, interleukin-6, superoxide dismutase, and selected matrix metalloproteinases can be distinguished.

Activating Notch1 signaling in melanoma-associated fibroblasts overcomes BRAF inhibitor resistance by disrupting cancer stem cell niches. This stromal-targeted approach represents a novel therapeutic strategy to complement surgical and systemic therapies in melanoma patients with drug-resistant disease.

P1, N=18, Not yet recruiting, Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

These tumors express diagnostic GIST markers (c-Kit and DOG1) and show significant response to the BRAF inhibitor dabrafenib. This model recapitulates key histopathological and molecular features of human BRAF-mutant GIST and provides a valuable platform for studying tumor initiation, progression, and therapeutic resistance. Importantly, it allows for preclinical testing of targeted therapies in BRAF GIST, offering new insights into treatment strategies.

As a risk factor, RAB7A relating to poor prognosis was identified in our study, and was a potential target for therapeutic agents such as PLX4720 and PD-0325901, while OXSM was the opposite. The 5-DRGs prognostic model can be used to assess the prognosis of patients with CC, and reflect the characteristics of their immune microenvironment. With RAB7A and OXSM as key determinants, this model provides a clinically applicable framework for risk stratification and personalized treatment guidance.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027