P2, N=40, Completed, Gustave Roussy, Cancer Campus, Grand Paris | Active, not recruiting --> Completed | Trial completion date: Dec 2022 --> Jan 2026

Compounds 20c and 21c exhibited potent inhibition of EGFR, with IC50 values of 71 and 64 nM, respectively, surpassing the reference erlotinib (IC50 = 80 nM). Moreover, compounds 20c and 21c exhibited BRAFV600E inhibitory action with IC50 values of 49 and 41 nM, respectively, which are somewhat less potent than the reference drug Vemurafenib...Compounds 20c and 21c showed a notable decrease in TNF-α and IL-6 levels compared with dexamethasone, suggesting an immunomodulatory effect. Molecular docking further validated the favorable orientation of 20c and 21c within the ATP-binding pocket of EGFR and BRAFV600E. These findings underscore compounds 20c and 21c as innovative dual-target scaffolds with significant promise for anticancer drug development.

P1, N=30, Active, not recruiting, Massachusetts General Hospital | Recruiting --> Active, not recruiting | Trial primary completion date: Sep 2025 --> Jul 2026

P2, N=280, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2026 --> Mar 2027 | Trial primary completion date: Mar 2026 --> Mar 2027

P2, N=134, Active, not recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2026 --> Feb 2027 | Trial primary completion date: Mar 2026 --> Feb 2027

P1, N=87, Active, not recruiting, Institute of Cancer Research, United Kingdom | Trial completion date: Oct 2023 --> Oct 2026

As expected, none of the BRAF KIAA1549 fusion+ pLGG tumors were sensitive to dabrafenib treatment. Two out of the three tumors demonstrated predicted sensitivity to trametinib, whereas one tumor did not. While no clinical correlates were measured in this proof-of-concept study, this mixed response to MEK inhibition on SLiCE is representative of heterogeneous real-world clinical responses. Together, these data demonstrate the feasibility of SLiCE to become a new functional biomarker of response in a tumor type where functional models are exceptionally rare, establishing a foundation for future individualized treatment strategies.

Furthermore, we show that secondary resistance induced by prolonged exposure of melanoma cells to BRAF inhibitor is associated with reduced FGD1 levels. These findings highlight the importance of FGD1 in melanoma progression and the acquisition of secondary resistance, positioning the FGD1-mediated signaling pathway as a putative therapeutic target.

Melanoma A375 (vemurafenib [VEM]-sensitive) and A375R (VEM-resistant) cells were exposed to eIF4Fi RocA at varying doses and durations in vitro...Combined CR-1-31-B, EZH2i, and AKT1i effectively overcame resistance to RocA and VEM resistance both in vitro and in vivo. The eIF4F complex inhibitor reactivates ERK1/2-EZH2 and AKT1 signaling pathways, resulting in resistance to both eIF4Fi and VEM. Combined administration of an eIF4Fi with EZH2 and AKT1 inhibitors effectively enhances sensitivity to both eIF4F complex and BRAF inhibitors.

High-risk patients had immunosuppressive TME and poor immunotherapy response, with Imatinib/PLX4720 showing potential efficacy. CD36/KIT overexpression promoted GC malignancy; their inhibition remodeled TME cytokines and, for the first time, activated the PA pathway to induce GC cell death.

The FDA recently granted accelerated approval of the small-molecule focal adhesion kinase (FAK) inhibitor (FAKi, defactinib) in combination with a RAF-MEK clamp inhibitor (avutometinib) for KRAS-mutated low-grade serous ovarian cancer developed by Verastem Inc. In this study, we review a short history of FAK, summarize ongoing combinatorial clinical trials, discuss potential mechanisms of action, and highlight studies showing that FAK activation is a chemo- and mechano-sensitive signaling hub driving tumor adaptive changes. Targeting FAK disarms tumor resistance through multiple mechanisms, which supports new biological insights and future clinical combinations.

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