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Activation of the PI3K/Akt pathway and chemotherapeutic resistance
Kip A West1, S Sianna Castillo, Phillip A Dennis
1Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, Building 8, Room 5101, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
Abstract:
The resistance of many types of cancer to conventional chemotherapies is a major factor undermining successful cancer treatment. In this review, the role of a signal transduction pathway comprised of the lipid kinase, phosphatidylinositol 3-kinase (PI3K), and the serine/threonine kinase, Akt (or PKB), in chemotherapeutic resistance will be explored. Activation of this pathway plays a pivotal role in essential cellular functions such as survival, proliferation, migration and differentiation that underlie the biology of human cancer. Akt activation also contributes to tumorigenesis and tumor metastasis, and as shown most recently, resistance to chemotherapy. Modulating Akt activity is now a commonly observed endpoint of chemotherapy administration or administration of chemopreventive agents. Studies performed in vitro and in vivo combining small molecule inhibitors of the PI3K/Akt pathway with standard chemotherapy have been successful in attenuating chemotherapeutic resistance. As a result, small molecules designed to specifically target Akt and other components of the pathway are now being developed for clinical use as single agents and in combination with chemotherapy to overcome therapeutic resistance. Specifically inhibiting Akt activity may be a valid approach to treat cancer and increase the efficacy of chemotherapy.
Insights
Targeting the phosphatidylinositol 3-kinase (PI3K)/Akt pathway can overcome cancer chemotherapeutic resistance. Inhibiting Akt shows promise for improving cancer treatment efficacy and overcoming drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chemotherapeutic resistance is a significant challenge in cancer treatment.
- The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is crucial for cancer cell survival, proliferation, migration, and differentiation.
- Aberrant activation of the PI3K/Akt pathway contributes to tumorigenesis, metastasis, and chemoresistance.
Purpose of the Study:
- To review the role of the PI3K/Akt pathway in chemotherapeutic resistance.
- To explore Akt activation as a mechanism underlying cancer drug resistance.
- To discuss the therapeutic potential of targeting the PI3K/Akt pathway.
Main Methods:
- Review of in vitro and in vivo studies investigating the PI3K/Akt pathway in cancer.
- Analysis of research on small molecule inhibitors targeting the PI3K/Akt pathway.
- Examination of clinical development of Akt inhibitors.
Main Results:
- PI3K/Akt pathway activation is implicated in multiple hallmarks of cancer, including resistance to chemotherapy.
- In vitro and in vivo studies demonstrate that combining PI3K/Akt inhibitors with standard chemotherapy can reduce chemoresistance.
- Small molecule inhibitors targeting Akt and other pathway components are under development for clinical use.
Conclusions:
- Modulating Akt activity is a key strategy in overcoming cancer chemotherapeutic resistance.
- Targeting the PI3K/Akt pathway, particularly Akt itself, offers a promising approach to enhance chemotherapy efficacy.
- Inhibiting Akt activity may serve as a valid therapeutic strategy for cancer treatment and improving patient outcomes.