Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin.

Journal Article (Journal Article)

PURPOSE: Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARgamma ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARgamma/carboplatin combination in these more relevant models of drug resistant non-small cell lung cancer. EXPERIMENTAL DESIGN: Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed. RESULTS: Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity. CONCLUSIONS: These data show that the PPARgamma ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.

Full Text

Duke Authors

Cited Authors

  • Girnun, GD; Chen, L; Silvaggi, J; Drapkin, R; Chirieac, LR; Padera, RF; Upadhyay, R; Vafai, SB; Weissleder, R; Mahmood, U; Naseri, E; Buckley, S; Li, D; Force, J; McNamara, K; Demetri, G; Spiegelman, BM; Wong, K-K

Published Date

  • October 15, 2008

Published In

Volume / Issue

  • 14 / 20

Start / End Page

  • 6478 - 6486

PubMed ID

  • 18927287

Pubmed Central ID

  • PMC2696122

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-08-1128


  • eng

Conference Location

  • United States