Targeting the Met-RIPK1 signaling axis to enforce apoptosis and necroptosis in colorectal cancer.

Resistance to cell death remains a critical challenge in the therapy of colorectal cancer (CRC). Smac mimetics (SM) are cytotoxic agents specifically designed to maximize tumor cell killing mediated via endogenous tumor necrosis factor (TNF). In CRC, however, SM lacked clinical activity for reasons that remain incompletely understood. Here, we report that the clinically approved tyrosine kinase inhibitor Cabozantinib potently sensitizes to SM by targeting a Met-RIPK1 signaling axis in CRC. Aberrant Met hampers the activation of RIPK1, which renders CRC cells resistant to TNF/SM-mediated apoptosis and necroptosis. In turn, Cabozantinib potently inhibits Met, thereby stabilizing RIPK1 expression and converting TNF into a robust pro-death signal. SM/Cabozantinib-based regimens demonstrated anti-tumor activity in vivo, and were effective in a heterogeneous panel of patient-derived CRC of diverse molecular subtypes. In addition, we show that it is feasible to modulate between apoptosis and necroptosis to overcome therapy resistance and foster anti-tumor immunity. In summary, this work provides novel biological insight into the mechanisms of SM resistance and warrants the combinatory use of SM and Cabozantinib to enhance apoptotic and necroptotic cell death in CRC.