Title:The Potential of PI3K/AKT/mTOR Signaling as a Druggable Target for Endometrial and Ovarian Carcinomas
Volume: 21
Issue: 10
Author(s): Csongor György Lengyel*, Sara Cecilia Altuna, Baker Shalal Habeeb, Dario Trapani and Shah Zeb Khan
Affiliation:
- Head and Neck Surgery, National Institute of Oncology Hungary, Budapest,Hungary
Keywords:
PI3K-AKT-mTOR pathway, precision medicine, targeted therapy, ovarian cancer, endometrial cancer, gynaecological
cancer, platinum resistance.
Abstract:
Aims: In this narrative review, we summarize the role and significance of PI3K-AKTmTOR
(PAM) pathway in ovarian and endometrial cancers, providing the most recent and relevant
literature on the topic and addressing options for targeting PAM along with future perspectives of drug
development.
Background: Alterations of the PAM-pathway are common in both endometrial and ovarian cancers,
and are described in specific histology-defined subtypes. PAM seems to be involved in critical steps of
endometrial and ovarian carcinogenesis, often mechanistically involved in the acquisition of a phenotype
of treatment resistance, which could be targetable. However, early clinical trials with PAMinhibitors
(PAMi) have provided disappointing results, particularly when non isoform-specific inhibitors
were tested in unselected populations, accompanied by an adverse safety profile. Since then, more
encouraging observations have been collected when targeting specific isoforms of PAM proteins with
more selective drugs, resulting in encouraging activity and more manageable toxicity.
Conclusion: Although the rationale of inhibiting the PAM-pathway has been demonstrated in several
promising preclinical studies, no Phase III clinical trial is available to demonstrate a significant benefit
of PAM-inhibitors. A way to manage targeted agents is to tailor their use to particular subpopulations
most likely to obtain a considerable benefit, namely pursuing an individualized, precision-medicine
approach.
