Condensates as a culprit in RAS activation and inhibitor resistance

Therapy resistance is a significant cause of death in patients treated with targeted cancer therapy in diverse oncogene-driven cancers. A better understanding of resistance mechanisms can lay the foundation for improving existing and developing new therapies. A recent elegant study published in Nature Chemical Biology sheds light on a new resistance mechanism. The authors define a novel role for ARAF, a member of the RAF protein family (A-, B-, C-RAF), that is distinct from its previously understood role as a RAS effector and MEK protein kinase in the MAPK pathway. They describe how ARAF sequesters active RAS at the plasma membrane in phase-separated condensates to sustain signaling and prevent inactivation by the RAS GTPase activating protein (GAP) neurofibromin 1 (NF1). This study underscores emerging roles for biomolecular condensates in cancer and highlights important implications for disrupting protein condensates to address treatment resistance to RAS (and RAS pathway) targeted therapies. The study also illuminates evolutionary functional distinction between the RAF proteins and indicates unique biology for ARAF in normal physiology and disease.