Inhibition of the PI3K pathway: hope we can believe in?
The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly activated pathways in human cancer and has roles in cell proliferation, apoptosis, protein synthesis, and metabolism. The PI3K pathway can be activated by amplification or activating mutation of upstream receptor tyrosine kinases, and by mutations or deletions downstream in the pathway. Trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER2), has been one of the most successful and most widely used targeted therapies. However, many HER2-positive cancers are not sensitive to HER2-based therapies or become resistant during treatment; downstream activation of the pathway is one of the causes of resistance. Because of the common activation of the PI3K pathway in cancer, compounds targeting proteins downstream in the pathway have been developed in recent years. The mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus have been shown to be beneficial in certain cancer types; many other inhibitors of the PI3K pathway are in various stages of clinical development. Ongoing research should clarify which molecular cancer subtypes are most susceptible to specific compounds and explore combinatorial approaches, ultimately leading to individualized patient treatment.
van der Heijden
Michiel S
MS
Division of Molecular Carcinogenesis, Center for Biomedical Genetics and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Bernards
René
R
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004789:Enzyme Activation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab