Notably, we observed differential immunomodulatory effects of cobimetinib in tumor-bearing mice compared to non-tumor-bearing immunocompetent mice. Our findings indicate that MEK inhibition is associated with ICD-related molecular alterations, and that cobimetinib may contribute to immune modulation in TNBC.

Building on this insight, we developed cobimetinib analogs with enhanced sensitization properties. Together, our findings provide a mechanistic framework for understanding the cellular determinants of DFG-out-stabilizing inhibitor sensitivity and offer strategies for optimizing synergistic RAF-MEK inhibitor combinations.

Human and murine models resistant to combined belvarafenib and cobimetinib exhibited elevated levels of ATF4 and MTHFD2 and were sensitive to sapanisertib. This study provides promising treatment opportunities for patients with non-BRAF-mutant melanomas, or those who relapse following belvarafenib and cobimetinib combination therapy.

P1, N=3, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: May 2027 --> Mar 2026 | Trial primary completion date: May 2027 --> Mar 2026

P3, N=510, Recruiting, Immuneering Corporation

P2, N=48, Not yet recruiting, Shanghai Fosun Pharmaceutical Industrial Development Co. Ltd.

P2, N=14, Active, not recruiting, University of Utah | N=29 --> 14

P1/2, N=229, Completed, Centre Leon Berard | Active, not recruiting --> Completed

The Hippo signaling pathway prevents unchecked cell growth, coordinates apoptosis, and preserves proper organ function. Furthermore, it bolstered the efficacy of the first-line drugs sorafenib and lenvatinib in inhibiting both hepatocellular carcinoma tumor growth and tumorigenesis. These findings establish a strategy for identifying and refining inhibitors of the YAP-TEAD complex in the treatment of cancers driven by aberrant YAP-TEAD activity.

P1/2, N=67, Recruiting, Recursion Pharmaceuticals Inc. | Trial completion date: Jul 2026 --> Sep 2027 | Trial primary completion date: Jul 2026 --> Jun 2027

KSR1 knockdown did not substantially affect ppERK responses to Type I½ RAF inhibitor (Encorafenib) in both cell types, whereas ppERK sensitivity slightly decreased for Type II RAFi (TAK-632) in MCF7 cells, aligning with simulations. The efficacy of MEKi (Cobimetinib) slightly increased in MCF7 cells following KSR1 knockdown but slightly decreased in PSN1 cells where higher MEKi concentrations were required to suppress ERK signaling, as predicted by the model. Our computational models predict, and experiments validate that in RAS-mutant cells, two conformation-specific RAF inhibitors used in combination suppress the ERK pathway more effectively than a combination of MEK and RAF inhibitors irrespective of KSR1 levels.

P1, N=42, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting