cp-673-451 and Lung-Neoplasms

Lack of insight into the identity of the cells that initiate metastasis hampers the development of antimetastatic therapies. Only a tiny fraction of tumor cells termed metastasis-initiating cells (MICs) are able to successfully seed metastases, causing recurrence and therapeutic resistance. Using metastasis models, we describe a subpopulation of MIC derivates from lung metastases that do not have proliferation advantages, express high levels of the PDGF receptors and EMT/stemness-related genes, and are unique in their ability to initiate metastasis. PDGF factors specifically boost the metastatic potential of MIC populations in a PDGFR-dependent manner. However, PDGFR inhibition preferentially suppresses lung metastases, but does not reduce the primary tumor burden. Thus, we found that PDGFR inhibition blocks AKT activation, whereas SGK1, which shares high-similarity kinase domain and overlap substrates with AKT overexpression remains active in MICs. SGK1 and PDGF signaling act in concert to promote metastatic formation, and SGK1 inhibition confers vulnerability to PDGFR inhibitors, also eliciting a powerful antitumor effect. In vivo, SGK1 inhibitors sensitize xenograft tumors to PDGFR-targeted therapies by reducing primary tumor growth and lung metastasis. Consequently, dual inhibition of PDGFR and SGK1 exhibited strong antitumor activities in established breast cancer cell lines in vitro and in vivo. Therefore, this approach not only provides insight into MIC transformation but also aids the design of improved therapeutic strategies for advanced breast cancer.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Benzoates; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Immediate-Early Proteins; Ligands; Lung Neoplasms; Mice, Inbred NOD; Mice, SCID; Models, Biological; Neoplasm Metastasis; Protein Serine-Threonine Kinases; Quinolines; Receptors, Platelet-Derived Growth Factor

Pericytes are pivotal mural cells of blood vessels and play an essential role in coordinating the function of endothelial cells. Previous studies demonstrated that Endostar, a novel endostatin targeting endothelial cells, can enhance the effect of radiotherapy (RT). The present study addressed whether inhibiting pericytes could potentially improve the efficacy of combined RT and Endostar therapy.. Platelet-derived growth factor beta-receptor inhibitor (CP673451) was chosen to inhibit pericytes and RT (12 Gy) was delivered. Lewis lung carcinoma-bearing C57BL/6 mice were randomized into 3 groups: RT, RT + Endo, and RT + Endo + CP673451. Subsequently, tumor microvessel density (MVD), pericyte coverage, tumor hypoxia, and lung metastasis were monitored at different time points following different therapies.. Compared to the other two groups, RT + Endo + CP673451 treatment markedly inhibited tumor growth with no improvement in the overall survival. Further analyses clarified that in comparison to RT alone, RT + Endo significantly reduced the tumor MVD, with a greater decrease noted in the RT + Endo + CP673451 group. However, additional CP673451 accentuated tumor hypoxia and enhanced the pulmonary metastasis in the combined RT and Endostar treatment.. Tumor growth can be further suppressed by pericyte inhibitor; however, metastases are potentially enhanced. More in-depth studies are warranted to confirm the potential benefits and risks of anti-pericyte therapy.

Topics: Angiogenesis Inhibitors; Animals; Benzimidazoles; Carcinoma, Lewis Lung; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Combined Modality Therapy; Endostatins; Female; Lung Neoplasms; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Pericytes; Quinolines; Receptor, Platelet-Derived Growth Factor beta; Recombinant Proteins; Time Factors

Platelet-derived growth factor receptors (PDGFRs) are abundantly expressed by stromal cells in the non-small cell lung cancer (NSCLC) microenvironment, and in a subset of cancer cells, usually with their overexpression and/or activating mutation. However, the effect of PDGFR inhibition on lung cancer cells themselves has been largely neglected. In this study, we investigated the anticancer activity of CP-673451, a potent and selective inhibitor of PDGFRβ, on NSCLC cell lines (A549 and H358) and the potential mechanism. The results showed that inhibition of PDGFRβ by CP-673451 induced a significant increase in cell apoptosis, accompanied by ROS accumulation. However, CP-673451 exerted less cytotoxicity in normal lung epithelial cell line BEAS-2B cells determined by MTT and apoptosis assay. Elimination of ROS by NAC reversed the CP-673451-induced apoptosis in NSCLC cells. Furthermore, CP-673451 down-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) probably through inhibition of PI3K/Akt pathway. Rescue of Nrf2 activity counteracted the effects of CP-673451 on cell apoptosis and ROS accumulation. Silencing PDGFRβ expression by PDGFRβ siRNA exerted similar effects with CP-673451 in A549 cells, and when PDGFRβ was knockdowned by PDGFRβ siRNA, CP-673451 produced no additional effects on cell viability, ROS and GSH production, Nrf2 expression as well as PI3K/Akt pathway activity. Specifically, Nrf2 plays an indispensable role in NSCLC cell sensitivity to platinum-based treatments and we found that combination of CP-673451 and cisplatin produced a synergistic anticancer effect and substantial ROS production in vitro. Therefore, these results clearly demonstrate the effectiveness of inhibition of PDGFRβ against NSCLC cells and strongly suggest that CP-673451 may be a promising adjuvant chemotherapeutic drug.

Topics: A549 Cells; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Cell Survival; Cisplatin; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation, Neoplastic; Glutathione; Humans; Lung Neoplasms; NF-E2-Related Factor 2; Oxidative Stress; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Quinolines; Reactive Oxygen Species; Receptor, Platelet-Derived Growth Factor beta; RNA Interference; Signal Transduction

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFbeta, which served as a model EMT system. The H358/TGFbeta cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFR-independent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFbeta receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.

Topics: Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Chromatography, Liquid; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Immunoblotting; Lung Neoplasms; Mesoderm; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Phosphorylation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Quinazolines; Quinolines; Receptor, ErbB-2; Receptor, ErbB-3; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Respiratory Mucosa; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Spectrometry, Mass, Electrospray Ionization; Thiophenes; Transforming Growth Factor beta; Tumor Cells, Cultured