Ownstream Akt activity (Fig. 5B and 5C). Due to the cross-talkOwnstream Akt activity (Fig. 5B

Ownstream Akt activity (Fig. 5B and 5C). Due to the cross-talk
Ownstream Akt activity (Fig. 5B and 5C). Due to the cross-talk between the individual members of the HER family or between the HER family and other RTKs, evidence indicates that targeting a single RTK is inadequate as a therapeutic modality in cancer therapy [48,49]. In gefitinib-resistant NSCLC cell lines, c-Met, an oncogenic RTK phosphorylates HER3 and leads to activation of the PI3K/ Akt pathway. Treatment of the resistant cells with a TKI specific for c-Met or gefitinib alone did not inhibit cell viability or affect HER3 and Akt phosphorylation. However, the combination of both drugs inhibited resistant cell growth and prevented HER3 and Akt phosphorylation [50]. Because MP470 does inhibit c-Met activation (data not shown), as well as c-Kit and Axl[51], it is likely that one or more of these RTKs cross-talk with the HER family members and activate them. Therefore, inhibition of HER1 and HER2 by Erlotinib and multi-targeted RTK inhibition by MP470 may explain the complete inhibition of the HER3/PI3K/Akt pathway by Erlotinib-MP470 combination in LNCaP cells. However, further studies are required to identify potential target(s) of MP470 in LNCaP cells for confirming this hypothesis.ConclusionMP470, a novel receptor tyrosine kinase inhibitor effectively inhibits cell proliferation in prostate cancer cell lines. When combined with Erlotinib, MP470 induced apoptosis and cell growth arrest with abolition of tumor growth in a dose-dependent manner in an LNCaP xenograft mouse model. The HER family and the phosphorylation of downstream Akt are inhibited by this novel TKI combination. Hence, blockade of HER family/ PI3K/Akt may represent a useful treatment modality for prostate cancer. The safety and efficacy of the MP470-Erlotinib combination is currently being evaluated in a Phase I clinical trial for refractory solid tumors and results are awaited with enthusiasm.Page 10 of(page number not for purchase Pan-RAS-IN-1 citation purposes)BMC Cancer 2009, 9:http://www.biomedcentral.com/1471-2407/9/Competing interestsThe authors except Dr. David Bearss declare that they have no competing interests. Dr. David Bearss has stocks and shares and is the Chief Scientific Officer at SuperGen.15. 16.Authors’ contributionsWQ and DM were responsible for designing the experiments, analyzing the data and drafting the manuscript. WQ also performed the apoptosis assay, immunoblotting, immunoprecipitation, immunohistochemistry, knockdown of HER2, cell cycle and phosphorylation antibody array analyses. LC, AS and KDC carried out MTS analyses. CJR did statistical analysis. JWS and DB gave advice on the experiments and manuscript. All authors read and approved the final manuscript.17. 18.19.20. 21.AcknowledgementsIt is our pleasure to acknowledge the National Foundation of Cancer Research for providing funding for this project. Also we wish to thank Dr. P. Tadikamalla and Dr. E. Mash of the Synthetic Chemistry Shared Service, Arizona Cancer Center for providing MP470. 22.23.
BMC CancerResearch articleBioMed CentralOpen AccessP-gp activity is a critical resistance factor against AVE9633 and DM4 cytotoxicity in leukaemia cell lines, but not a major mechanism of chemoresistance in cells PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28388412 from acute myeloid leukaemia patientsRuoping Tang*1,2, Simy Cohen2, Jean-Yves Perrot1, Anne-Marie Faussat2, Claudia Zuany-Amorim3, Zora Marjanovic1, Hamid Morjani4, Fanny Fava1,2, Elise Corre1, Ollivier Legrand1,2 and Jean-Pierre Marie1,Address: 1Assistance Publique ?H itaux de Paris, H ital H el Dieu, 1 plac.