Targeting cytokine networks in KRAS-driven tumorigenesis

KRAS is one of the most commonly mutated oncogenes in human tumors, and is typically associated with aggressive disease. Despite intensive study and years of effort, KRAS has remained refractory to targeted inhibition. Given the challenge of inhibiting KRAS directly, current approaches to KRAS targeted therapy have involved the disruption of downstream signaling pathways. However, combinations of drugs that target RAF/MEK and PI3K/AKT signaling have failed to live up to expectations in the clinic. Here we summarize the evidence that the cytokine signaling circuitry of KRAS-driven tumors represents an equally tractable drug target. Indeed, the incorporation of novel therapeutics that disrupts these cytokine signaling networks may hold the key to overcoming this seemingly impenetrable treatment barrier.