Deconstructing feedback-signaling networks 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.
Carracedo
Arkaitz
A
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Harvard Medical School, Boston, Massachusetts 02215, USA.
Baselga
Jose
J
Pandolfi
Pier Paolo
PP
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D006801:Humans; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors