GRB2 (growth factor receptor-bound protein 2) mRNA

Class

Liposomal antisense oligonucleotide

Pathway

Blocks Grb2 translation, downregulating Ras/MAPK and PI3K/AKT signaling

GRB2 (growth factor receptor-bound protein 2) is an adaptor protein that has no enzymatic activity of its own but serves as a molecular link between activated cell-surface growth factor receptors and two major intracellular signaling cascades: the Ras/MAPK pathway and the PI3K/AKT pathway. These pathways control cell proliferation, survival, and metabolism, and their inappropriate activation is a recurring feature of many cancers, including leukemias driven by mutant or overactive receptor tyrosine kinases. Rather than inhibiting a single mutated kinase, this mechanism uses an antisense oligonucleotide—a short synthetic strand of nucleic acid designed to bind the messenger RNA (mRNA) encoding GRB2—to prevent the cell from producing the protein at all. Without GRB2, signals from multiple upstream receptors are less able to reach the Ras and PI3K branches, dampening the proliferative and survival signaling that tumor cells depend on. Because GRB2 sits at a convergence point downstream of several different receptors, this approach can theoretically act on tumors driven by more than one oncogenic input, rather than being tied to a single mutation. The oligonucleotide is packaged in a lipid-based carrier (liposome) to protect it from degradation and improve its delivery into target cells. This general strategy is of interest in blood cancers where Ras/MAPK and PI3K/AKT signaling are frequently dysregulated.