Deconstructing feedback-signalingnetworks to improve anticancer therapy with mTORC1 inhibitors

Targeting mTOR complex 1 (mTORC1), which regulates general protein translation, represents one of the most attractive approaches to treating cancer, since upregulation of this pathway is a common hallmark in many tumors. Nevertheless, the use of rapamycin and its analogs in the clinic has revealed that mTORC1 pathway is embedded in a network of signaling cross-talks and feedbacks which might reduce its effectiveness in cancer. We have recently described a novel signaling feedback stemming from mTORC1 inhibition, which leads to the activation of ERK-MAPK (MAPK) pathway. The observation that MAPK is activated by rapamycin and its analogs in vitro, in mouse models, and cancer patient biopsies sets the rationale for the combined use of MAPK and mTORC1 inhibitors in cancer therapy. In this extra-view, we integrate our findings into the mTORC1 signaling network and discuss its relevance for the design of combinatorial therapies with mTORC1 inhibitors.