# A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition

## TL;DR

This paper shows that FAK signaling is crucial for melanoma cells with a Rac1 mutation to resist cancer drugs, and combining two inhibitors could help treat this aggressive form of melanoma.

## Contribution

The study identifies FAK signaling as a novel therapeutic target in Rac1-driven melanoma resistant to MAPK inhibitors.

## Key findings

- Rac1-driven melanomas use multiple resistance mechanisms, including reduced BRAF/MEK dependence and activation of Jun and p38 MAP kinase pathways.
- Rac1-driven melanoma cells show partial reliance on YAP/TAZ signaling and a dependency on focal adhesion kinase (FAK) signaling.
- Combining RAF/MEK clamp avutometinib with FAK inhibitor defactinib effectively suppresses growth of Rac1-driven melanoma cells.

## Abstract

The Rac1 P29S hotspot mutation in cutaneous melanoma is associated with resistance to MAPK pathway inhibitors (MAPKi) and worse clinical outcomes. Moreover, activation of Rac1 guanine exchange factors (GEFs) also promotes MAPKi-resistance, particularly in undifferentiated melanoma cells. Here we delineate mechanisms of Rac1-driven MAPKi-resistance and identify strategies to inhibit the growth of this class of cutaneous melanomas. We find that Rac1-driven melanomas manifest pleiotropic resistance mechanisms including (i) reduced dependence on BRAF/MEK, (ii) activation of alternative MAPK pathways utilizing Jun kinase and p38 MAP kinase, and (iii) a partial reliance on YAP/TAZ signaling. Importantly, although Rac1-driven melanoma cells display reduced dependence on BRAF/MEK, they are not completely ERK-independent. Additionally, the presence of activated Rac1 appears to create a dependency on focal adhesion kinase (FAK) signaling in undifferentiated melanoma cells. Therefore, despite the pleiotropic mechanisms of Rac1-driven MAPKi resistance, we find that combined inhibition of RAF and MEK with the RAF/MEK clamp avutometinib and FAK with the FAK inhibitor defactinib is a promising approach for suppressing the growth of Rac1-driven melanoma cells. Thus, the avutometinib plus defactinib combination, which is currently being investigated for brain metastatic cutaneous melanoma may also have utility against Rac1-driven MAPKi-resistance in heavily pre-treated, advanced disease.