Am J Cancer Res 2012;2(2):178-191
Original Article
Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling
module in melanoma therapy
Ali R Jazirehi, Peter B Wenn, Mohsen Damavand
Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen School of
Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA.
Received December 1, 2011; accepted December 20, 2011; Epub January, 2012; Published February 1, 2012
Abstract: The PI3Kinase/AKT/mTOR signaling module is implicated in various cellular functions including cell survival, growth
and proliferation, glucose metabolism, apoptosis, migration, and angiogenesis. Increased expression of AKT and its up- and
downstream regulators is linked to several types of cancer. Aberrant expression of AKT is observed in nearly 60% of melanomas
culminating in apoptosis resistance via deactivation of apoptotic molecules Bad and Caspase-9. Through cross-talk with NF-κB,
ERK1/2, JNK and p38MAPK signaling pathways, AKT induces a plethora of cellular effects often leading to tumor development
and progression. Due to frequently observed resistance to other common cancer treatments such as chemotherapy,
immunotherapy, and radiation, and the detrimental consequences of constitutive activation of the PI3Kinase/AKT/mTOR
signaling module, targeted inhibition of the effectors and substrates involved in this module has become a viable and attractive
option for molecular targeted therapy in melanoma. Pharmacological inhibitors of various components of this module, either
alone or in combination with other agents, have shown significant decrease in proliferation, tumorigenesis, cell growth and
survival of various tumors in phases I and II clinical trials. Some inhibitors have even received their Food and Drug
Administration (FDA) approval. This review summarizes the current knowledge on this module, its cross-talk with other major
cell survival pathways and its targeted inhibition for therapeutic purposes in melanoma. (AJCR0000096).
Keywords: PI3Kinase, AKT, mTOR, PTEN, melanoma, targeted therapy, signal transduction, apoptosis, resistance
Address all correspondence to:
Ali Jazirehi, CLS, PhD
Division of Surgical Oncology
CHS 54-140
University of California, Los Angeles
10833 LeConte Avenue
Mail code: 178218
Los Angeles, CA 90095
Phone: (310) 206-8509
Fax: (310) 267-2679
ajazirehi@mednet.ucla.edu
Original Article
Therapeutic implications of targeting the PI3Kinase/AKT/mTOR signaling
module in melanoma therapy
Ali R Jazirehi, Peter B Wenn, Mohsen Damavand
Department of Surgery, Division of Surgical Oncology, and the Jonsson Comprehensive Cancer Center, David Geffen School of
Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA, USA.
Received December 1, 2011; accepted December 20, 2011; Epub January, 2012; Published February 1, 2012
Abstract: The PI3Kinase/AKT/mTOR signaling module is implicated in various cellular functions including cell survival, growth
and proliferation, glucose metabolism, apoptosis, migration, and angiogenesis. Increased expression of AKT and its up- and
downstream regulators is linked to several types of cancer. Aberrant expression of AKT is observed in nearly 60% of melanomas
culminating in apoptosis resistance via deactivation of apoptotic molecules Bad and Caspase-9. Through cross-talk with NF-κB,
ERK1/2, JNK and p38MAPK signaling pathways, AKT induces a plethora of cellular effects often leading to tumor development
and progression. Due to frequently observed resistance to other common cancer treatments such as chemotherapy,
immunotherapy, and radiation, and the detrimental consequences of constitutive activation of the PI3Kinase/AKT/mTOR
signaling module, targeted inhibition of the effectors and substrates involved in this module has become a viable and attractive
option for molecular targeted therapy in melanoma. Pharmacological inhibitors of various components of this module, either
alone or in combination with other agents, have shown significant decrease in proliferation, tumorigenesis, cell growth and
survival of various tumors in phases I and II clinical trials. Some inhibitors have even received their Food and Drug
Administration (FDA) approval. This review summarizes the current knowledge on this module, its cross-talk with other major
cell survival pathways and its targeted inhibition for therapeutic purposes in melanoma. (AJCR0000096).
Keywords: PI3Kinase, AKT, mTOR, PTEN, melanoma, targeted therapy, signal transduction, apoptosis, resistance
Address all correspondence to:
Ali Jazirehi, CLS, PhD
Division of Surgical Oncology
CHS 54-140
University of California, Los Angeles
10833 LeConte Avenue
Mail code: 178218
Los Angeles, CA 90095
Phone: (310) 206-8509
Fax: (310) 267-2679
ajazirehi@mednet.ucla.edu
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American Journal of Cancer Research
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