173O - Optimizing therapeutic combinations of a selective MEK 1/2 inhibitor (pimasertib) with PI3K/Mtor inhibitors or with multi-targeted kinase inhibitors...

Date 29 September 2012
Event ESMO Congress 2012
Session Biomarkers in breast and colorectal cancer
Topics Biomarkers
Colon Cancer
Rectal Cancer
Lung and other Thoracic Tumours
Presenter Erika Martinelli
Authors E. Martinelli1, T. Troiani2, F. Morgillo3, E. D'Aiuto4, L. Ciuffrida5, S. Costantini5, L. Vecchione6, V. De Vriendt7, S. Tejpar7, F. Ciardiello2
  • 1Dipt. Di Internistica Clinica E Sperimentale, Second University of Naples, 80131 - Naples/IT
  • 2Dip. Medico Chirurgico Di Internistica, Second University of Naples, 80131 - Naples/IT
  • 3Dipartimento Di Internistica F Magrassi A Lanzara, Second University of Naples, 80131 - Naples/IT
  • 4Immunology Department, Second University of Naples, 80131 - Naples/IT
  • 5Pharmacology Department, Second University of Naples, 80131 - naples/IT
  • 6Digestive Oncology Unit - Department Human Genetics, University Hospital Gasthuisberg, BE-3000 - Leuven/BE
  • 7Digestive Oncology Unit, University Hospital Gasthuisberg, BE-3000 - Leuven/BE



The RAS/RAF/MEK/MAPK and the PTEN/PI3K/AKT/mTOR pathways are key intracellular signal transduction pathways for the control of survival and proliferation in human cancer cells. Selective inhibitors of different transducer molecules in these pathways have being developed as molecular targeted anti-cancer therapies.


The in vitro and in vivo antitumor activity of pimasertib, a selective MEK ½ inhibitor, alone or in combination with a PI3K inhibitor (PI3Ki), a mTOR inhibitor (everolimus), or with multitargeted kinase inhibitors (sorafenib and regorafenib) were tested in a panel of eleven human lung and colon cancer cell lines.


Following pimasertib treatment, the cancer cell lines were classified as pimasertib-sensitive (IC50 for cell growth inhibition of approximately 0.001 µM) or pimasertib-resistant (IC50 for cell growth inhibition above 3 µM). Evaluation of basal gene expression profiles by microarrays identified a series of 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, G1 phase arrest and induction of apoptosis with a 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 combination 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 it is possible to overcome intrinsic resistance to MEK inhibition by the dual blockade of MAPK and PI3K pathways.


All authors have declared no conflicts of interest.