Repurposing of mTOR Complex Inhibitors Attenuates MCL-1 and Sensitizes to PARP Inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• MCL-1, an antiapoptotic BCL-2 family member, is vital for cell survival and possesses DNA repair functions.
• Targeting protein synthesis via mTOR complex (mTORC) inhibitors offers a potential strategy to modulate MCL-1 activity.
• Homologous recombination (HR) repair is a critical pathway in maintaining genomic stability and a target for cancer therapy.

Purpose of the Study:

• To investigate if mTORC inhibitors deplete MCL-1, suppress HR repair, and sensitize cancer cells to PARP inhibitors.
• To evaluate the efficacy of combining mTORC inhibitors with olaparib in preclinical cancer models.
• To explore the underlying mechanisms of MCL-1 depletion and HR repair suppression by mTORC inhibitors.

Main Methods:

• Treatment of various cancer cell lines (colorectal carcinoma, SCLC, GBM) with mTORC inhibitors (everolimus, AZD2014).
• Assessment of MCL-1 levels, 4EBP1 phosphorylation, and DNA repair foci (γ-H2AX, 53BP1, BRCA1, RPA, Rad51).
• In vitro clonogenic survival assays and in vivo xenograft studies using combination therapy with olaparib.

Main Results:

• Everolimus and AZD2014 differentially depleted MCL-1 in cancer cells, with AZD2014 effective in GBM.
• Combination therapy with mTORC inhibitors and olaparib significantly inhibited tumor growth and clonogenic survival.
• Reintroduction of MCL-1 rescued cancer cell survival, confirming MCL-1's role in sensitivity.
• mTORC inhibitors plus olaparib impaired HR repair markers and induced necroptosis.

Conclusions:

• mTORC inhibitors effectively deplete MCL-1, suppressing homologous recombination DNA repair.
• This depletion sensitizes cancer cells to PARP inhibitors, demonstrating therapeutic potential.
• Targeting MCL-1's DNA repair function via mTORC inhibition presents a novel strategy for cancer therapy, potentially enhancing antitumor immunity through necroptosis.