Rheb/mTOR activation and regulation in cancer: novel treatment strategies beyond rapamycin

Area of Science:

• Cell Biology
• Oncology
• Biochemistry

Background:

• Mammalian target of rapamycin (mTOR) exists in two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2).
• mTORC1 is inhibited by rapamycin, while mTORC2 is insensitive to this drug.
• Both mTOR complexes are crucial for cellular homeostasis and the proliferation of various cancer types.

Purpose of the Study:

• To review current and emerging therapeutic strategies targeting mTOR complexes for cancer treatment.
• To explore novel approaches for inhibiting mTORC1 beyond rapamycin.
• To investigate the potential of targeting mTORC1 activity to sensitize cancer cells to DNA damage and endoplasmic reticulum (ER) stress.

Main Methods:

• Literature review of mTOR signaling pathways and their role in cancer.
• Analysis of existing and experimental drugs targeting mTOR, including rapamycin, ATP-competitive inhibitors, and PI3K/mTOR dual inhibitors.
• Examination of alternative mTORC1 inhibition strategies like amino acid depletion and Rheb GTPase inhibition.
• Review of studies on the interplay between mTORC1 activation, DNA damage, and ER stress in cancer cells.

Main Results:

• Rapamycin and its analogs show limited efficacy in many cancers.
• ATP-competitive mTOR kinase inhibitors and PI3K/mTOR dual inhibitors are direct approaches.
• Alternative mTORC1 inhibition methods include asparaginase and farnesyl transferase inhibitors or statins.
• mTORC1 activation can induce and sensitize cells to DNA damage and ER stress.

Conclusions:

• Targeting mTORC1 offers potential clinical benefits for cancer treatment.
• Exploiting mTORC1's role in sensitizing cells to stress may allow for tailored therapies.
• Existing cancer drugs could be repurposed to treat tumors with high mTORC1 activity.