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The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance

Melissa M Pham1, Emily Hinchcliff2, Monica Avila1

  • 1From the Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer, Houston, TX.

Cancer Journal (Sudbury, Mass.)
|December 14, 2021
PubMed

Insights

Poly(ADP-ribose) polymerase inhibitors (PARPi) show promise in treating solid tumors with DNA repair defects. However, resistance to PARPi therapy is a growing challenge, necessitating research into combination treatments to improve patient outcomes.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Poly(ADP-ribose) polymerase inhibitors (PARPi) leverage synthetic lethality in tumors with homologous recombination repair (HRR) defects.
  • Clinical success is established for PARPi in BRCA-mutated breast and ovarian cancers, and in tumors with "BRCAness" features.
  • Limited durability of response and emerging PARPi resistance pose significant clinical challenges.

Purpose of the Study:

  • To review the molecular mechanisms underlying PARPi resistance.
  • To examine current clinical trials investigating combination therapies to overcome PARPi resistance.
  • To discuss future strategies for enhancing PARPi clinical efficacy.

Main Methods:

  • Review of preclinical models detailing mechanisms of PARPi resistance.
  • Analysis of ongoing clinical trials evaluating combination therapies.
  • Discussion of future research directions.

Main Results:

  • Key resistance mechanisms include HRR restoration, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic alterations.
  • Combination strategies combining PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, PI3K/AKT inhibitors, MEK inhibitors, and epigenetic modifiers are under investigation.
  • Understanding resistance mechanisms is crucial for developing effective retreatment strategies.

Conclusions:

  • PARPi resistance is a complex phenomenon involving multiple molecular pathways.
  • Combination therapies hold promise for overcoming PARPi resistance and improving long-term patient outcomes.
  • Further research is essential to optimize treatment strategies for patients with PARPi-resistant tumors.

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