Targeting the PI3K/AKT/mTOR Pathway in Cancer Therapy: A Current Evaluation of Next-Generation mTOR Inhibitors

Öz

The PI3K/AKT/mTOR signaling pathway plays a crucial role in cancer development. mTOR, a serine/threonine kinase, regulates several fundamental cellular processes, including cell growth, metabolism, translation, the cell cycle, and cell survival. Dysregulation of the PI3K/AKT/mTOR pathway has been associated with the development of various cancer types, and its hyperactivation leads to abnormal cancer cell growth and metastasis. Specifically, the two main mTOR complexes, mTORC1 and mTORC2, play key roles in supporting cancer cell survival and proliferation. This review highlights the significance of mTOR as a key target for cancer therapy, investigating how mTOR inhibitors can suppress cancer cells by modulating this pathway. While mTOR inhibitors, such as rapamycin and its derivatives, show promise in cancer treatment, clinical success has been limited by drug resistance and toxicity issues. Therefore, the need for more specific and effective inhibitors is emphasized. In particular, dual inhibitor strategies, such as those targeting both PI3K and mTOR, are highlighted for their ability to inhibit both the mTORC1 and mTORC2 complexes, thus effectively curbing cancer cell growth and metabolism. However, further research is required to fully realize the clinical potential of these inhibitors. Additionally, clinical studies on the inhibition of the PI3K/AKT/mTOR pathway suggest that combination therapies with chemotherapy and other targeted treatments yield better outcomes compared to monotherapies. This combination approach is considered more effective in overcoming resistance mechanisms in cancer cells.

Anahtar Kelimeler

• PI3K/AKT/mTOR pathway
• mTOR inhibitors
• dual inhibitors
• mTORC1
• mTORC2

Kanser Tedavisinde PI3K/AKT/mTOR Yolunun Hedeflenmesi: Yeni Nesil mTOR İnhibitörlerine Güncel Bir Değerlendirme

Öz

PI3K/AKT/mTOR sinyal yolu, kanser gelişiminde kritik bir role sahiptir. mTOR, hücre büyümesi, metabolizma, translasyon, hücre döngüsü ve hayatta kalma gibi birçok temel hücresel sürecin düzenlenmesinde görev alan bir serin/treonin kinazıdır. PI3K/AKT/mTOR sinyal yolunun bozulması, çeşitli kanser türlerinin gelişimiyle ilişkilendirilmiştir ve bu yolun aşırı aktivasyonu, kanser hücrelerinin anormal büyümesine ve metastaz yapmasına neden olur. Özellikle mTOR'un iki ana kompleksi olan mTORC1 ve mTORC2, kanser hücrelerinin hayatta kalma ve proliferasyonunu destekleyen anahtar rol oynar. Derlemede, mTOR’un kanser tedavisi için önemli bir hedef olduğu vurgulanmakta ve mTOR inhibitörlerinin bu yolağı baskılayarak kanser hücrelerini nasıl etkilediği incelenmektedir. Rapamisin ve türevleri gibi mTOR inhibitörlerinin, kanser tedavisinde umut vaat ettiği ancak ilaç direnci ve toksisite gibi sorunlar nedeniyle klinik başarılarının sınırlı kaldığı bilinmektedir. Bu sebeple, daha spesifik ve etkili inhibitörlerin geliştirilmesi gerektiği vurgulanmaktadır. Özellikle PI3K/mTOR gibi ikili inhibitör stratejilerinin, hem mTORC1 hem de mTORC2 komplekslerini hedef alarak kanser hücrelerinin büyümesini ve metabolizmasını baskıladığı, ancak bu inhibitörlerin klinik kullanımı için daha fazla araştırmaya ihtiyaç duyulduğu ifade edilmektedir. Ayrıca, PI3K/AKT/mTOR yolunun inhibisyonu üzerine yapılan klinik çalışmaların, kemoterapi ve diğer hedefe yönelik tedavilerle kombinasyonunun daha iyi sonuçlar verdiği ve tekli tedavilere göre daha etkili olduğu da vurgulanmıştır.

Anahtar Kelimeler

• PI3K/AKT/mTOR yolu
• mTOR inhibitörleri
• ikili inhibitörler
• mTORC1
• mTORC2

Kaynakça

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