The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key regulators of proliferation and survival in human cancer cells. Selective inhibitors of different transducer molecules in these ...pathways have been developed as molecular targeted anti‐cancer therapies. The in vitro and in vivo anti‐tumor activity of pimasertib, a selective MEK 1/2 inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multi‐targeted kinase inhibitors (sorafenib and regorafenib), that block also BRAF and CRAF, were tested in a panel of eight human lung and colon cancer cell lines. Following pimasertib treatment, cancer cell lines were classified as pimasertib‐sensitive (IC50 for cell growth inhibition of 0.001 µM) or pimasertib‐resistant. Evaluation of basal gene expression profiles by microarrays identified several genes that were up‐regulated in pimasertib‐resistant cancer cells and that were involved in both RAS/RAF/MEK/MAPK and PTEN/PI3K/AKT/mTOR pathways. Therefore, a series of combination experiments with pimasertib and either PI3Ki, everolimus, sorafenib or regorafenib were conducted, demonstrating a synergistic effect in cell growth inhibition and induction of apoptosis with sustained blockade in MAPK‐ and AKT‐dependent signaling pathways in pimasertib‐resistant human colon carcinoma (HCT15) and lung adenocarcinoma (H1975) cells. Finally, in nude mice bearing established HCT15 and H1975 subcutaneous tumor xenografts, the combined treatment with pimasertib and BEZ235 (a dual PI3K/mTOR inhibitor) or with sorafenib caused significant tumor growth delays and increase in mice survival as compared to single agent treatment. These results suggest that dual blockade of MAPK and PI3K pathways could overcome intrinsic resistance to MEK inhibition.
What's new?
Drugs that block key regulators of cell proliferation and survival form the basis of targeted anticancer therapy but are highly susceptible to resistance‐conferring mutations in their targets. This limitation may be overcome with various combinations of drugs, as shown here with pimasertib, a small‐molecule MEK1/MEK2 inhibitor. Microarray analysis reveals that the combination of pimasertib with PI3K/mTOR or multi‐targeted kinase inhibitors prevents proliferation and induces apoptosis in pimasertib‐resistant HCT15 colorectal cancer and H1975 non‐small cell lung cancer cells. Combined blockade of key intracellular pathways produced similar effects in mice with tumors established from the two pimasertib‐resistant lines.
The present study assesses the accuracy with which the subject specific coordinates of the hip joint centre (HJC) in a pelvic anatomical frame can be estimated using different methods. The functional ...method was applied by calculating the centre of the best sphere described by the trajectory of markers placed on the thigh during several trials of hip rotations. Different prediction methods, proposed in the literature and in the present investigation, which estimate the HJC of adult subjects using regression equations and anthropometric measurements, were also assessed. The accuracy of each of the above-mentioned methods was investigated by comparing their predictions with measurements obtained on a sample of 11 male adult able-bodied volunteers using roentgen stereophotogrammetric analysis (RSA), assumed to provide the true HJC locations. Prediction methods estimated the HJC location at an average rms distance of 25–30
mm. The functional method performed significantly better and estimated HJCs within a rms distance of 13
mm on average. This result may be confidently generalised if the photogrammetric experiment is carefully conducted and an optimal analytical approach used. The method is therefore suggested for use in motion analysis when the subject’s hip range of motion is not limited. In addition, the facts that it is not an invasive technique and that it has relatively small and un-biased errors, make it suitable for regression equations identification with no limit to sample size and population typology.
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