Biomarkers, Endometrial cancer, KRAS, MEK inhibitor, PI3K inhibitor, PIK3CA, PTEN loss, Protein signalling.
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.
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.
Medical Molecular Biology | Medical Sciences
Aslan 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
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.