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Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro.
Aslan, Ozlem; Cremona, Mattia; Morgan, Clare; Cheung, Lydia W; Mills, Gordon B; Hennessy, Bryan T
<p>The original article is available at <a href=""></a></p> <p><strong>BACKGROUND:</strong> 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.</p> <p><strong>METHODS:</strong> 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.</p> <p><strong>RESULTS:</strong> 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.</p> <p><strong>CONCLUSIONS:</strong> 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.</p>
Keyword(s): Biomarkers; Endometrial cancer; KRAS; MEK inhibitor; PI3K inhibitor; PIK3CA; PTEN loss; Protein signalling.; Medical Molecular Biology; Medical Sciences
Publication Date:
Type: Journal article
Peer-Reviewed: Yes
Institution: Royal College of Surgeons in Ireland
Citation(s): 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
Publisher(s): BioMed Central
File Format(s): application/pdf
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First Indexed: 2018-02-25 07:16:00 Last Updated: 2018-02-25 07:16:00