Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer

Claudia Fumarola; Mara A Bonelli; Pier Giorgio Petronini; Roberta R Alfieri

doi:10.1016/j.bcp.2014.05.011

Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer

Biochem Pharmacol. 2014 Aug 1;90(3):197-207. doi: 10.1016/j.bcp.2014.05.011. Epub 2014 May 24.

Authors

Claudia Fumarola¹, Mara A Bonelli², Pier Giorgio Petronini³, Roberta R Alfieri⁴

Affiliations

¹ Unit of Experimental Oncology, Clinical and Experimental Medicine Department, University of Parma, Via Volturno 39, 43126 Parma, Italy. Electronic address: claudia.fumarola@unipr.it.
² Unit of Experimental Oncology, Clinical and Experimental Medicine Department, University of Parma, Via Volturno 39, 43126 Parma, Italy. Electronic address: mara.bonelli@unipr.it.
³ Unit of Experimental Oncology, Clinical and Experimental Medicine Department, University of Parma, Via Volturno 39, 43126 Parma, Italy. Electronic address: piergiorgio.petronini@unipr.it.
⁴ Unit of Experimental Oncology, Clinical and Experimental Medicine Department, University of Parma, Via Volturno 39, 43126 Parma, Italy. Electronic address: roberta.alfieri@unipr.it.

PMID: 24863259
DOI: 10.1016/j.bcp.2014.05.011

Abstract

While PI3K/AKT/mTOR pathway is altered in a variety of cancers including non small cell lung cancer, abnormalities in this pathway are more common in squamous cell lung carcinoma than in adenocarcinoma of the lung. Moreover, aberrant activation of PI3K/AKT/mTOR pathway is one of the mechanisms of acquired resistance to EGFR-TK inhibitors in patients with adenocarcinoma carrying EGFR activating mutations. Several inhibitors of the PI3K pathway are undergoing evaluation in preclinical and clinical studies. These include pan and selective inhibitors of PI3K, AKT inhibitors, rapamycin and rapalogs for mTOR inhibition, dual mTORC1-mTORC2 inhibitors and dual PI3K-mTOR inhibitors. This review focuses on recent preclinical and clinical data on the efficacy of PI3K pathway inhibitors in NSCLC either as monotherapy approach or in combination with chemotherapy or with drugs that target other signaling transduction pathways.

Keywords: AKT; NSCLC; PI3K; SQCLC; mTOR.

Publication types

Review

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / adverse effects
Antineoplastic Agents / therapeutic use
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / metabolism
Drug Resistance, Neoplasm
Enzyme Inhibitors / administration & dosage
Enzyme Inhibitors / adverse effects
Enzyme Inhibitors / therapeutic use
Humans
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / metabolism
Molecular Targeted Therapy* / adverse effects
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / metabolism
Phosphatidylinositol 3-Kinase / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction / drug effects*
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
Enzyme Inhibitors
Neoplasm Proteins
Phosphoinositide-3 Kinase Inhibitors
MTOR protein, human
Phosphatidylinositol 3-Kinase
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases