%0 Journal Article %A Aslan, Ozlem %A Cremona, Mattia %A Morgan, Clare %A Cheung, Lydia W %A Mills, Gordon B. %A Hennessy, Bryan T. %D 2019 %T Preclinical evaluation and reverse phase protein Array-based profiling of PI3K and MEK inhibitors in endometrial carcinoma in vitro. %U https://repository.rcsi.com/articles/journal_contribution/Preclinical_evaluation_and_reverse_phase_protein_Array-based_profiling_of_PI3K_and_MEK_inhibitors_in_endometrial_carcinoma_in_vitro_/10786310 %2 https://repository.rcsi.com/ndownloader/files/19299227 %K Biomarkers %K Endometrial cancer %K KRAS %K MEK inhibitor %K PI3K inhibitor %K PIK3CA %K PTEN loss %K Protein signalling. %K Molecular Medicine %X

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.

%I Royal College of Surgeons in Ireland