Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer.
Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. We found that tumor samples from patients with biopsy-accessible solid tumors of advanced disease treated with RAD001, a rapamycin derivative, showed an administration schedule-dependent increase in activation of the MAPK pathway. RAD001 treatment also led to MAPK activation in a mouse model of prostate cancer. We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway. Significantly, pharmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors, currently employed as single agents in the clinic, for the treatment of human cancers.
Carracedo
Arkaitz
A
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, Massachusetts, USA.
Ma
Li
L
Teruya-Feldstein
Julie
J
Rojo
Federico
F
Salmena
Leonardo
L
Alimonti
Andrea
A
Egia
Ainara
A
Sasaki
Atsuo T
AT
Thomas
George
G
Kozma
Sara C
SC
Papa
Antonella
A
Nardella
Caterina
C
Cantley
Lewis C
LC
Baselga
Jose
J
Pandolfi
Pier Paolo
PP
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068338:Everolimus; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000201:enzymology* / Q000378:metabolism; D011506:Proteins; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus