Colorectal cancers are the second highest cause of cancer-related death worldwide, and nearly half of all cases are driven by mutations to the KRAS protein, which controls signaling through the RAF/MEK/ERK pathway. Drugs that target this pathway have not, however, proved effective against KRAS-mutant cancers. Further, tumor cell heterogeneity and plasticity—which is driven by epigenetic mechanisms—hamper the efficacy of targeted therapies and contribute to drug resistance in colorectal cancer (CRC). Given all this, researchers led by Ludwig Harvard’s Karen Cichowski hypothesized that simultaneously targeting epigenetic and traditional oncogenic signals might push CRCs into a therapeutically vulnerable state. They reported in an August issue of Cancer Discovery that inhibitors of the histone methyltransferase, EZH2—an epigenetic enzyme that is overexpressed in multiple solid tumors—synergize with various RAS pathway inhibitors to induce dramatic tumor regression in mouse models of CRC. The combination, Karen and her colleagues showed, cooperatively suppresses the WNT signaling pathway, driving differentiation of CRC cells by altering their epigenetic state. The agents also induce expression of BMF, a BCL2-family protein that drives apoptotic cell death, to kill the more differentiated cells. The researchers note that their study reveals a promising strategy for treating advanced colorectal cancer, describes its mechanism of action and illustrates a paradigm for epigenetics-based cancer therapy.
Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers
Cancer Discovery, 2024 August 12