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Published on: July 25, 2020
Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition
1Translational Research Institute, 37 Kent Street, Woolloon gabba, Brisbane QLD 4102, Australia. mingtat.ling@qut.edu.au.
Abstract:
The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is one of the most frequently activated signaling pathways in prostate cancer cells, and loss of the tumor suppressor PTEN and amplification of PIK3CA are the two most commonly detected mechanisms for the activation of these pathways. Aberrant activation of PI3K/Akt/mTOR has been implicated not only in the survival and metastasis of prostate cancer cells but also in the development of drug resistance. As such, selective inactivation of this pathway may provide opportunities to attack prostate cancer from all fronts. However, while preclinical studies examining specific inhibitors of PI3K or mTOR have yielded promising results, the evidence from clinical trials is less convincing. Emerging evidence from the analyses of some solid tumors suggests that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, may achieve better anti-cancer outcomes. In this review, we will summarize the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds, and their potential to serve as the next generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs.
Insights
Dual PI3K/mTOR inhibitors show promise for treating prostate cancer, especially drug-resistant forms. These inhibitors target key signaling pathways involved in cancer cell survival and metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway is frequently activated in prostate cancer.
- Loss of PTEN and PIK3CA amplification are common drivers of this pathway activation.
- Aberrant PI3K/Akt/mTOR signaling promotes prostate cancer cell survival, metastasis, and drug resistance.
Purpose of the Study:
- To review the mechanisms of action of dual PI3K/mTOR inhibitors.
- To evaluate the effectiveness of these inhibitors as monotherapy or in combination treatments.
- To explore their potential as next-generation therapies for prostate cancer, particularly in resistant cases.
Main Methods:
- Review of preclinical studies and clinical trial data on PI3K/mTOR inhibitors.
- Analysis of emerging evidence from solid tumor studies.
- Summary of mechanisms of action and therapeutic strategies.
Main Results:
- Preclinical studies of PI3K or mTOR inhibitors show promise.
- Clinical trial evidence for single-target inhibitors is less convincing.
- Dual PI3K/mTOR inhibitors may offer improved anti-cancer outcomes.
Conclusions:
- Dual PI3K/mTOR inhibitors represent a potential therapeutic strategy for prostate cancer.
- These inhibitors may overcome resistance to current chemotherapies.
- Further investigation is warranted for their clinical application in prostate cancer patients.
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