Therapeutic targeting and patient selection for cancers with homologous recombination defects

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• DNA double-strand breaks (DSBs) are critical DNA lesions repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR).
• Defects in HR genes predispose individuals to cancer and enhance sensitivity to DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors.
• Accurate patient selection is vital for effective PARP inhibitor therapy in HR-deficient cancers.

Purpose of the Study:

• To provide a mechanistic overview of the HR pathway.
• To review the therapeutic strategies for HR-deficient cancers, emphasizing PARP inhibition in BRCA1/2-mutated breast and ovarian cancers.
• To discuss acquired resistance mechanisms and combination therapies involving PARP inhibitors.

Main Methods:

• Review of the homologous recombination repair pathway.
• Analysis of current treatment strategies for HR-deficient cancers, including PARP inhibitors.
• Discussion of resistance mechanisms and combination therapies.

Main Results:

• BRCA1/2 mutations are key indicators for PARP inhibitor eligibility, but not all patients respond.
• HR deficiency from other genetic or epigenetic factors may also predict response to PARP inhibitors.
• Current patient selection is limited, highlighting the need for broader eligibility criteria.

Conclusions:

• PARP inhibitors offer a promising treatment avenue for HR-deficient cancers, particularly those with BRCA1/2 mutations.
• Expanding patient selection beyond BRCA1/2 mutations to include functional HR read-outs is essential.
• Functional assays assessing HR repair capacity and replication fork stability are proposed for optimal patient stratification.