New drug target could overcome melanoma resistance to standard therapies
Researchers have identified a protein called INPP5E as a key driver of aggressive melanomas, suggesting a new way to attack tumors that resist existing drugs. The finding could expand treatment options for a cancer that kills tens of thousands annually and opens a new market for precision therapies targeting a previously unexplored biological pathway.
Originaltitel: ICMT supports BRAF <sup>V600E</sup> -driven tumor growth by membrane targeting of the CAAX protein INPP5E
Isoprenylcysteine carboxyl methyltransferase (ICMT) catalyzes C-terminal methylation of prenylated CAAX proteins, a final processing step promoting membrane association and signaling. Although ICMT has been pursued to disrupt RAS membrane targeting, its role in BRAF V600E -driven cancers and critical substrates remains unclear. Here, genetic and pharmacologic (UCM-1336) ICMT inhibition suppressed proliferation and invasion in BRAF V600E -mutant melanoma cells and reduced tumor growth in xenografts and mice. ICMT knockdown inhibited proliferation of BRAF-inhibitor-resistant melanoma cells. We identify INPP5E as an ICMT-dependent substrate: ICMT inhibition reduced INPP5E methylation, displaced it from membranes, and increased PI(4,5)P 2 . Forced INPP5E membrane targeting partially rescued growth defects caused by ICMT inhibition. These findings implicate an ICMT-INPP5E-axis that supports BRAF V600E -driven tumor growth.