The potential of pi3k/akt/mtor signaling as a druggable target for endometrial and ovarian carcinomas

Csongor György Lengyel, Sara Cecilia Altuna, Baker Shalal Habeeb, Dario Trapani, Shah Zeb Khan

Research output: Contribution to journalReview articlepeer-review

Abstract

Aims: In this narrative review, we summarize the role and significance of PI3K-AKT-mTOR (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 PAM-inhibitors (PAMi) have provided disappointing results, particularly when non isoform-specific inhibi-tors 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.

Original languageEnglish
Pages (from-to)946-961
Number of pages16
JournalCurrent Drug Targets
Volume21
Issue number10
DOIs
Publication statusPublished - 2020

Keywords

  • Endometrial cancer
  • Gynaecological cancer
  • Ovarian cancer
  • PI3K-AKT-mTOR pathway
  • Platinum resistance
  • Precision medicine
  • Targeted therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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