title: Signaling mechanisms that suppress the cytostatic actions of rapamycin.
abstract: While rapamycin and the "rapalogs" Everolimus and Temsirolimus have been approved for clinical use in the treatment of a number of forms of cancer, they have not met overarching success. Some tumors are largely refractory to rapamycin treatment, with some even undergoing an increase in growth rates. However the mechanisms by which this occurs are largely unknown. The results presented here reveal novel cell-signaling mechanisms that may lead to this resistance. The absence of TGFβ signaling results in resistance to rapamycin. Additionally, we observed that treatment of some cancer cell lines with rapamycin and its analogs not only potentiates mitogenic signaling and proliferation induced by HGF, but also stimulates the pro-survival kinase Akt. Together, the data show that the effectiveness of rapamycin treatment can be influenced by a number of factors and bring to light potential biomarkers for the prediction of responsiveness to treatment, and suggest combination therapies to optimize rapalog anticancer efficacy.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States of America; University of Florida-Health Cancer Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Jahn
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States of America; University of Florida-Health Cancer Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Law
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States of America; University of Florida-Health Cancer Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Corsino
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States of America; University of Florida-Health Cancer Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Davis
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States of America; University of Florida-Health Cancer Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Harrison
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida, United States of America; University of Florida-Health Cancer Center, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Law
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D054697:Cytostatic Agents / Q000494:pharmacology*; D000068338:Everolimus; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D054697:Cytostatic Agents; D016212:Transforming Growth Factor beta; C401859:temsirolimus; D000068338:Everolimus; D020123:Sirolimus