Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Francesca Corti, Federico Nichetti, Alessandra Raimondi, Monica Niger, Natalie Prinzi, Martina Torchio, Elena Tamborini, Federica Perrone, Giancarlo Pruneri, Maria Di Bartolomeo, Filippo de Braud, Sara Pusceddu

Research output: Contribution to journalReview articlepeer-review

Abstract

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches. The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes. Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy. This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.

Original languageEnglish
Pages (from-to)45-55
Number of pages11
JournalCancer Treatment Reviews
Volume72
DOIs
Publication statusPublished - Jan 2019

Keywords

  • AKT
  • Biliary tract cancers
  • Cholangiocarcinoma
  • mTOR
  • PI3K
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging

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