Checkpoint adaptation in recombination-deficient cells drives aneuploidy and resistance to genotoxic agents

Area of Science:

• Molecular Biology
• Genetics
• Cancer Research

Background:

• Human cancers often have DNA repair gene mutations, making DNA damaging agents a viable treatment.
• Therapy resistance is a significant challenge in cancer treatment, necessitating research into resistance mechanisms.

Purpose of the Study:

• To investigate the molecular pathways driving resistance to DNA damaging agents in cancer.
• To explore therapeutic strategies targeting resistance mechanisms.

Main Methods:

• Utilizing recombination-defective diploid yeast as a model system.
• Inducing genotoxic stress and observing cellular responses, including checkpoint adaptation and aneuploidy.
• Employing pharmacological and genetic inhibition of adaptation pathways.
• Investigating the efficacy of TORC1 inhibition with rapamycin in combination with DNA damaging agents.

Main Results:

• Genotoxic challenges induce checkpoint adaptation in nearly all yeast cells, leading to aneuploid cells with whole chromosome losses that are resistant to the initial challenge.
• Inhibiting adaptation, either pharmacologically or genetically, significantly reduces the generation of resistant cells.
• Aneuploid phenotypes of resistant cells can be specifically targeted to induce cytotoxicity.
• TORC1 inhibition with rapamycin, combined with DNA damaging agents, effectively prevents checkpoint adaptation and the proliferation of aneuploid resistant cells.

Conclusions:

• Checkpoint adaptation leading to aneuploidy is a key mechanism of resistance to DNA damaging agents.
• Targeting adaptation pathways, particularly through TORC1 inhibition, presents a promising strategy to overcome therapeutic resistance in cancer.
• Combined therapy of DNA damaging agents and rapamycin can prevent the emergence and growth of resistant cancer cells.