Researchers in Kian-Huat Lim’s lab at Washington University have developed a therapeutic strategy to target TPL2 in RAS-mutated cancers, which should work synergistically with chemotherapy and radiation. As TPL2 (MAP3K8) is necessary for upstream activation of both MAPK and NF-κB signaling in RAS-mutated cancer cells, it provides a more appealing target for inhibitors than MEK/ERK or NF-κB alone.
In RAS-mutated cancers, inhibiting RAS-induced MAPK signaling is a common therapeutic strategy. However, tumor cells evade those therapeutics by activating NF-κB signaling instead, so targeting a protein upstream of both pathways represents a more effective strategy. The researchers have also identified several additional cancer types where mutated TPL2 is constitutively active.
Stage of Research
The researchers have identified and validated TPL2 as a therapeutic target for pancreatic cancer in vitro using a commercially-available TPL2 inhibitor. Ongoing research involves lead generation and in vivo testing.
- Dodhiawala PB, Khurana N, Zhang D, Cheng Y, … Lin K-H. (2020). TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations. Journal of Clinical Investigation, 130(9):4771-4790.
- Therapeutic in RAS-mediated cancers
- Central to both MAPK and NF-κB signaling pathways