Rational Combinations of PARP Inhibitors with HRD-Inducing Molecularly Targeted Agents

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• A growing number of cancer patients exhibit wild-type BRCA, homologous recombination proficiency, or resistance to poly (ADP-ribose) polymerase (PARP) inhibitors.
• These patients represent a significant population who may not respond to standard PARP inhibitor monotherapy.

Approach:

• This review synthesizes current research on targeted inhibitors impacting homologous recombination (HR) pathways.
• We examine inhibitors of angiogenesis, epigenetic regulators, PI3K, MAPK, and other cellular signaling pathways.
• The focus is on their potential to induce homologous recombination deficiency (HRD).

Key Points:

• Targeted agents can be utilized to induce HRD in tumors not typically considered sensitive to PARP inhibition.
• Combinatorial strategies involving PARP inhibitors alongside these targeted agents show promise.
• This approach broadens the therapeutic landscape for PARP inhibitor-based treatments.

Conclusions:

• Inducing HRD through targeted therapies offers a viable strategy to overcome resistance and expand the application of PARP inhibitors.
• Combinatorial approaches hold potential for treating cancers with wild-type BRCA or HR proficiency.
• Further clinical investigation is warranted to validate these combinatorial strategies.