Abstract C30: A KRAS pathway activation index predicting response to MEK inhibitors in patient-derived tumor xenografts.
Authors: Peille Anne-Lise , Maier Armin , Foucault Frederic , Krumbach Rebekka , Kees Tim , Giesemann Torsten , Metz Thomas , Metcalfe Thomas , Fiebig Heinz-Herbert , Vuaroqueaux Vincent 
Published: August 2014

Abstract
Introduction: MEK 1/2 inhibitors (MEKi) are promising compounds for the treatment of cancer due to frequent activation of the RAS/MAPK/ERK oncogenic pathway. CI-1040 and PD0325901 are newly developed MEKi that are currently being tested in clinical trials. In the present study, we investigated MEKi response in different tumor types and we determined whether an index of KRAS pathway activation (K-PAI) could predict response to MEKi. Material and Methods: CI-1040 and PD0325901 were tested using an ex vivo 3D Tumor Clonogenic Assay (TCA) in a panel of 63 patient-derived tumor xenografts (PDX) covering 15 tumor histotypes. The K-PAI was determined by identifying gene expression patterns (Affymetrix HGU133 plus 2.0 arrays) associated with activation of the pathway and KRAS mutational status (determined by Sanger sequencing). Results: The absolute activities (IC50) of CI-1040 and PD0325901 correlated in most of the tumor models tested (r=0.87). Most of the melanomas were sensitive to both MEKi tested, whereas variable response profiles were observed in colon cancers and non-small cell lung cancers (NSCLC). Ovarian and pancreatic cancer xenografts displayed in most instances weak responses. The KRAS and BRAF statuses were significantly associated with MEKi IC50 (p=0.0001 and p=0.0002, respectively). The melanomas which frequently displayed BRAF mutations (13/21), were highly sensitive to MEKi treatment, whereas ovarian and pancreatic tumors, which frequently harbored KRAS mutations (1/3 and 2/2), were resistant. Moreover, we found that the K-PAI correlated significantly with MEKi IC50 (r&gt;0.5, p&lt;0.0001 for CI-1040 and PD0325901).= Melanomas with low K-PAI values were highly sensitive to MEKi treatment whereas ovarian and pancreatic tumors with high K-PAI values were resistant. Interestingly, the K-PAI was also predictive of response to MEKi treatment for tumors expressing wild-type BRAF and KRAS.Conclusion: This large ex vivo PDX study showed that tumor sensitivity to MEKi is related to histology and to RAS pathway activation. KRAS and BRAF mutations were predictive of MEKi response (resistance and sensitivity, respectively). These results are consistent with published data on cell lines and on small patient cohorts and demonstrate that PDX are adequate models to test targeted drugs such as MEKi. The correlation of tumor sensitivity to MEKi and the RAS pathway activation level (K-PAI) should be further evaluated in ex vivo 3D assays utilizing PDXs or with an in vivo study, to be able to better stratify patients when testing the predictive potential of K-PAI in clinical trials.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C30.
Citation Format: Anne-Lise Peille, Armin Maier, Frederic Foucault, Rebekka Krumbach, Tim Kees, Torsten Giesemann, Thomas Metz, Thomas Metcalfe, Heinz-Herbert Fiebig, Vincent Vuaroqueaux. A KRAS pathway activation index predicting response to MEK inhibitors in patient-derived tumor xenografts. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C30.