Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.
Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.
Department of Radiation Oncology; Clinical Biology Laboratory, Department of Radiation Oncology, Advance Centre for Treatment Research & Education in Cancer, Tata Memorial Center, Navi Mumbai, India.
Jayant S
JS
Goda
Tejaswini
T
Pachpor
Trinanjan
T
Basu
Supriya
S
Chopra
Vikram
V
Gota
D066246:ErbB Receptors / Q000096:biosynthesis; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D015689:Oncogene Protein p21(ras) / Q000096:biosynthesis; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
D017320:HIV Protease Inhibitors; D011838:Radiation-Sensitizing Agents; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D015689:Oncogene Protein p21(ras)