Pharmacologic inhibition of mTOR antagonizes the cytotoxic activity of pemetrexed in non-small cell lung cancer.
OBJECTIVE
Pemetrexed, an inhibitor of thymidylate synthase (TS) and additional folate-dependent enzymes, is clinically active in patients suffering from "non-squamous" non-small cell lung cancer (NSCLC). High expression of TS has been implied as biomarker predictive of resistance to pemetrexed. Against this background, we studied whether inhibition of mTOR could lower expression of TS and thus sensitize NSCLC cells to pemetrexed.


RESULTS
Using squamous cell carcinoma and adenocarcinoma NSCLC cell lines, we observed that constitutive TS expression levels failed to correlate with sensitivity to growth inhibition or apoptosis imposed by pemetrexed in vitro. Interestingly, pemetrexed strongly induced TS RNA and protein expression in all cell lines. The allosteric "rapalogue" mTOR inhibitor everolimus suppressed constitutive, but not pemetrexed-induced TS expression. Surprisingly, cotreatment with everolimus protected NSCLC cells against pemetrexed-induced apoptosis. This resulted in increased long-term clonogenic survival of NSCLC cells treated with pemetrexed plus everolimus as compared to pemetrexed alone. No such negative interaction was observed when everolimus was combined with recombinant TRAIL, a proliferation-independent proapoptotic agent.


CONCLUSIONS
Rapalogues may suppress the antitumor activity of pemetrexed by slowing cell cycle progression. This should be considered when combining pemetrexed and mTOR inhibitors in NSCLC treatment.
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany.
Boyka
B
Markova
Patricia S
PS
Hähnel
Stefan
S
Kasper
Stephan
S
Herbertz
Martin
M
Schuler
Frank
F
Breitenbuecher
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000068338:Everolimus; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D000068437:Pemetrexed; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D000970:Antineoplastic Agents; D005971:Glutamates; D007166:Immunosuppressive Agents; D000068437:Pemetrexed; D006147:Guanine; D000068338:Everolimus; D013940:Thymidylate Synthase; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D005472:Fluorouracil; D020123:Sirolimus