PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases

Int J Mol Sci. 2019 Nov 18;20(22):5792. doi: 10.3390/ijms20225792.


The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention.

Keywords: APDS; PI3K; PROS; PTEN hamartoma; TSC; brain penetration; cancer; mTOR inhibitor; mTORopathy; overgrowth syndrome.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rare Diseases / drug therapy*
  • Rare Diseases / metabolism
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • TOR Serine-Threonine Kinases / metabolism


  • Small Molecule Libraries
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt