Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro.
BACKGROUND: The phosphoinositide-3-kinase (PI3K) pathway is the most commonly activated pathway in cancers due to mutations at multiple nodes and loss of PTEN. Furthermore, in endometrial cancer (EC), PI3K and RAS/RAF/MEK/MAPK (RAS/MAPK herein) pathway mutations frequently co-exist. We examined the role of PI3K and RAS/MAPK pathway mutations in determining responsiveness to therapies targeted to these pathways in vitro in EC.
METHODS: 13 EC cell lines were profiled for their PI3K pathway and KRAS mutational and PTEN protein status and treated with one MEK- and two PI3K- targeted inhibitors alone and in combination. Expression and phosphorylation of 66 proteins were evaluated by Reverse-Phase-Protein-Array (RPPA) in 6 EC cell lines to identify signalling changes in these pathways in response to therapy.
RESULTS: PTEN protein loss and the absence of any tested pathway mutations are dominant negative predictors of sensitivity to MEK inhibition. KRAS-mutated cells were most sensitive to MEK inhibition, but significantly more resistant to PI3K inhibition than KRAS-wild-type cell lines. Combinations of PI3K and MEK inhibitors showed synergy or additivity in all but two cell lines tested. Treatment of KRAS-mutated cells with PI3K inhibitors and treatment of PTEN-low cells with a MEK inhibitor were most likely to induce activation of MEK/MAPK and AKT, respectively, likely indicative of feedback-loop regulation.
CONCLUSIONS: MEK inhibition may be a promising treatment modality, not just for ECs with mutated KRAS, but also for those with retained PTEN. Up-regulation of MEK/MAPK signalling by PI3K inhibition, and up-regulation of AKT activation by MEK inhibition may serve as potential biomarkers of likely responsiveness to each inhibitor.
This research was funded by the Irish Cancer Society’s first Collaborative Cancer Research Centre BREAST-PREDICT (grant CCRC13GAL), the National Cancer Institute (grants P30 CA016672 and P50 CA098258), the North East Cancer Research and Education Trust, and the Health Research Board/Science Foundation Ireland (HRB-SFI) Translational Research Award (grant TRA 2010/08). The funding body had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
CommentsThe original article is available at www.biomedcentral.com
Published CitationAslan O, Cremona M, Morgan C, Cheung LW, Mills GB, Hennessy BT. Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro. BMC Cancer. 2018;18(1):168
- Molecular Medicine
- Beaumont Hospital