Memorial Sloan-Kettering Cancer Center has received a USD 1.71 million NCI OT2 award to pursue a counterintuitive approach to colorectal cancer treatment: rather than solely inhibiting oncogenic signaling, deliberately overactivating it to lethal effect.
The REWIRE-CAN project, led by Karuna Ganesh, targets the three major signaling pathways dysregulated in colorectal cancer — WNT, MAPK, and PI3K — based on preclinical evidence that cancer cells tolerate only a narrow range of pathway activity. Push signaling beyond that threshold, the hypothesis holds, and cells die. The program pairs this hyperactivation strategy with a parallel effort to shift cancer cells between functional states, aiming to sensitize tumors to existing chemotherapy and targeted agents. The approach will be tested using patient-derived organoids, functional genetic screens, and in vivo models, with a stated goal of advancing candidates toward clinical proof-of-concept before the award period closes in April 2027.
Colorectal cancer remains among the most treatment-resistant solid tumors at advanced stages, and its rising incidence in adults under 50 has intensified pressure on the field to move beyond standard KRAS inhibition and checkpoint immunotherapy. The REWIRE-CAN strategy is mechanistically distinct from approved targeted therapies such as sotorasib or adagrasib, which suppress MAPK output rather than amplifying it. Whether the hyperactivation concept translates from organoid models to patients remains to be demonstrated.