Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and Carboplatin

Abstract

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 (PPARg ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARg/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 PPARg 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.Lung cancer is the leading cause of cancer-related deaths. There are over 210,000 cases of lung cancer diagnosed and over 160,000 deaths in the United States alone (1, 2). The most common type of lung cancer is non -small cell lung cancer (NSCLC), which comprises over 75% of the cases (3). Despite advances in multimodality therapies, <15% of patients with NSCLC survive beyond 5 years of initial diagnosis. Activating mutations of the KRAS proto-oncogene are among the most common genetic alterations in NSCLC (4 -8). These mutations lead to the constitutive activation of downstream signaling transduction pathways including RAF and phosphatidylinositol-3-OH kinase. These pathways, in turn, regulate proliferation and survival. In addition to playing a role in the development of lung cancer, mutations in KRAS predict a poor outcome and a poor response to conventional therapy such as platinumbased drugs, as well as targeted therapy (4, 9 -12). The

Repression of NHE1 Expression by PPARγ Activation Is a Potential New Approach for Specific Inhibition of the Growth of Tumor CellsIn vitroandIn vivo

“…In light of the recent study showing that an antisense therapy targeting NHE1 gene in gastric cancer decreased invasive capacity, and loss of cloning efficiency, and tumorigenicity in nude mice (43), the repressive effect of PPARγ activation on NHE1 expression presents a window of opportunity for exploiting PPARγ agonists for selectively tailoring the expression of NHE1 to achieve a favorable therapeutic response. In addition, synergy between rosiglitazone and platinum-based drugs in several different cancers both in vitro and using transplantable and chemically induced "spontaneous" tumor models was recently reported (44,45). Pertinent to this, we have shown previously that decreasing NHE1 expression sensitizes tumor cells to anticancer drugs (18) and Supplementary Fig.…”

PPARγ agonists enhance ET-743–induced adipogenic differentiation in a transgenic mouse model of myxoid round cell liposarcoma

“…20 mice were assigned to each cohort and followed for survival and/or tumor burden, as defined by tumor greater than 1 cm in longest dimension and/ or animal distress. Notably, we purposely chose low ends of the reported spectrum of in vivo usage of these drugs to allow for concurrent usage without exacerbating toxicity (23)(24)(25). We observed 4 survival patterns (P = 6.5 × 10 -35 , χ 2 distribution, 3 degrees of freedom; Figure 3A).…”

PPARγ is functionally expressed in clear cell renal cell carcinoma

“…Unfortunately, no significant effect could be observed when troglitazone alone was administered in patients with metastatic colorectal cancer included in a phase II clinical trial (46). Recent reports demonstrated a synergy between PPARÁ ligands and current anticancer therapies such as fluorouracil (47), carboplatin (48,49) or tamoxifen (50). Thus, it would be interesting to evaluate the effect of PPARÁ ligand in clinical trials, alone or in combination with other molecules.…”