P1, N=267, Recruiting, Pfizer | Trial completion date: Aug 2030 --> Oct 2029 | Trial primary completion date: Feb 2029 --> Apr 2028

The cytotoxic effects of three MAPK pathway inhibitors (selumetinib, vemurafenib, dabrafenib) were assessed in ATC cell lines and xenograft models via viability assays and 18F-FDG PET/CT. Furthermore, MAPK pathway inhibitors increased radioiodine uptake in ATC cells. The MAPK pathway inhibitors enhance NIS function through two mechanisms: upregulation of NIS expression and increased ARF4-mediated NIS membrane transport.

Notably, we discover that RAF265, a compound already approved by the FDA, effectively inhibits USP10 activity, leading to decreased SCD1 expression and lipogenesis, which then suppresses tumor growth and enhances ferroptosis in both in vitro and in vivo models of HNSCC. Collectively, these results underscore the critical role of the E2F4/USP10/SCD1 pathway in modulating ferroptosis and driving HNSCC progression, suggesting that targeting this axis with RAF265 may offer a promising strategy for therapeutic intervention in this malignancy.

Our results highlight that both hypoxia and therapeutic pressure modulate tumor progression in a complex, context-dependent manner.

Notably, δ-TT restored responsiveness to vemurafenib, indicating a synergistic interaction in resistant melanoma cells. Overall, these findings provide mechanistic evidence supporting a potential role for δ-TT as a modulator of drug response and support further investigation of δ-TT-based combination strategies to overcome therapeutic resistance in melanoma.

In contrast, compounds 16, 17, and 22 displayed marked cellular activity despite limited B-RAF inhibition, indicating potential contributions from alternative kinases or yet unidentified off-target mechanisms. The large DSF Tm shifts observed established the poorly exploited pyrimido[4,5-d]pyrimidines as interesting ATP mimetic scaffolds for kinase inhibitor development.

Screening for drugs also revealed AKT1, TP53, and PIK3R4 as druggable hubs, and many drugs (e.g., Everolimus, Dabrafenib, Trabectedin) showing high-affinity interactions. The study discovers new prognostic markers (ATG4A, GABARAPL2, GAPDH) and druggable targets, which could lead to better risk stratification and smarter drug repurposing. While restricted to in silico analyses, the integrative approach provides a basis for subsequent laboratory confirmation and translational development.

Whilst the link between LCH and several haematological malignancies is documented, the mechanism is still unclear. In this case, the LCH most likely developed from an already abnormal myeloid compartment and highlights the need for clinical vigilance and appropriate investigation, where effective treatments for these conditions exist.

Vemurafenib markedly inhibited HCC cell proliferation and metastasis, which was accompanied by a pronounced induction of apoptosis and G0/G1 phase cell-cycle arrest. At the signaling level, these cellular responses were linked to enhanced JNK activation and the suppression of AKT phosphorylation, suggesting that vemurafenib may serve as a potential therapeutic agent for HCC.

We have recently demonstrated that a RAC1 mutation (RAC1 P34R) can induce the formation of PGCCs in aggressive thyroid cancer cells from a patient undergoing dabrafenib treatment, leading to resistance to therapy...By targeting RAC1's integrative functions, researchers may unlock new avenues for preventing PGCC-mediated recurrence and metastasis, offering a promising strategy to improve long-term outcomes in cancer treatment. This review outlines the diverse functions of RAC1 that may contribute to both the formation and sustained maintenance of PGCCs across various tumor types.

Furthermore, EMT-high tumors exhibited distinct drug sensitivity profiles, including reduced responsiveness to conventional chemotherapeutics and increased sensitivity to agents such as camptothecin and dabrafenib. Collectively, these findings identify PHTF2 and SNAI1 as key regulators of EMT and tumor cell proliferation in thyroid cancer, and suggest that EMT-driven TME remodeling contributes to immune evasion and therapeutic resistance, thereby revealing EMT-associated vulnerabilities as potential targets for precision therapy.