title: Overcoming mTOR inhibition-induced paradoxical activation of survival signaling pathways enhances mTOR inhibitors' anticancer efficacy.
abstract: The mammalian target of rapamycin (mTOR) has emerged as an important cancer therapeutic target. Several mTOR inhibitors are currently being tested in cancer clinical trials. Both PI3K/Akt and MEK/ERK signaling regulate mTOR axis. However, inhibition of mTOR activates Akt survival signaling, which in turn attenuates mTOR inhibitors' anticancer efficacy. We are interested in developing strategies for enhancing mTOR-targeted cancer therapy. In this study, we report that mTOR inhibition also induced activations of the MEK/ERK signaling pathway in some cancer cell lines after a prolonged treatment. The combination of rapamycin with the MEK inhibitor U0126 significantly enhanced growth inhibitory effects of cancer cells, suggesting that MEK/ERK activation may counteract mTOR inhibitors' anticancer efficacy. Similarly, the combination of an mTOR inhibitor with the EGF receptor inhibitor erlotinib synergistically inhibited the growth of both human cancer cells in cell cultures and xenografts in nude mice. Moreover, the presence of erlotinib suppressed rapamycin-induced phosphorylation of Akt, ERK and eIF4E as well, implying that erlotinib can suppress mTOR inhibition-induced feedback activation of several survival signaling pathways including Akt, ERK and eIF4E. Thus, we suggest a therapeutic strategy for enhancing mTOR-targeted cancer therapy by preventing mTOR inhibition-induced feedback activation of several survival mechanisms.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.forename: Natalyn
authors.initials: N
authors.lastname: Hawk
authors.forename: Ping
authors.initials: P
authors.lastname: Yue
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism* / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C401859:temsirolimus; D000069347:Erlotinib Hydrochloride; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus