Dual Targeting of Akt and MAPK Pathways With Capivasertib and B-Raf Inhibitors Synergistically Suppresses Tumor Growth in B-Raf-Mutated Melanoma Models

Abstract

Resistance to B-Raf inhibitors in melanoma poses a significant challenge to effective treatment. This study investigates the synergistic effects of capivasertib, an Akt pathway inhibitor, in combination with B-Raf inhibitors (vemurafenib and encorafenib) in B-Raf-mutated melanoma models. Combination index analysis demonstrated strong synergy between capivasertib and B-Raf inhibitors in melanoma cells. In contrast, combinations of capivasertib with standard chemotherapeutics were antagonistic, underscoring the specificity of the interaction. Mechanistic studies revealed that capivasertib effectively suppressed Akt signaling. Synergism was abolished in Akt-overexpressing cells, confirming Akt's role in the observed combination effects. The combination treatments significantly reduced tumor growth, with tumor volumes in the capivasertib-vemurafenib and capivasertib-encorafenib groups reduced by ~70% relative to control. Notably, this inhibition was sustained for at least 8 weeks, with tumors in the combination groups remaining minimal, while those in the control group reached maximal size by Week 4. Systemic toxicity analyses revealed no significant changes in body weight or serum markers of pancreatic, kidney, or liver function. These findings establish capivasertib and B-Raf inhibitor combinations as a safe and effective strategy for overcoming resistance B-Raf-mutated melanoma, providing new insights into the potential of dual pathway targeting.

Keywords: Akt; B‐Raf inhibitors; capivasertib; melanoma; therapy resistance.