Overcoming Resistance to PARP Inhibition

  • Somaira Nowsheen
  • Fen XiaEmail author
Part of the Resistance to Targeted Anti-Cancer Therapeutics book series (RTACT, volume 20)


PARP inhibitors are one of the success stories of targeted cancer therapy. In the last few years, these drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of breast and ovarian cancers. PARP inhibitors are useful in the treatment of DNA double-strand break repair deficient tumors such as those with BRCA1 or BRCA2 mutations. In this chapter, we discuss the pathophysiology of breast and ovarian cancers in association with DNA repair and genomic instability. We focus our discussion on the use of PARP inhibitors in these malignancies. We also discuss how the tumors gain resistance to these agents, including utilizing strategies such as restoration of homologous recombination-mediated DNA double-strand break repair pathway and stabilization of replication forks. We review possible approaches for overcoming resistance to PARP inhibitors including targeting protein kinases and alternate signaling pathways, exploiting cell cycle regulation, and drug pumps. We end with the benefits of novel therapies, their limitations and work that remains to be done.


DNA damage response DNA repair PARP inhibitor Breast cancer Ovarian cancer Resistance Radiotherapy Targeted therapy BRCA p53 





Protein kinase B


BRCA1-associated RING domain


Bromodomain and extra-terminal


Breast cancer gene 1


Breast cancer gene 2


Cyclin-dependent kinase 12


C-terminal binding protein interacting protein


Food and Drug Administration


Human epidermal growth factor receptor 2


Hepatocyte growth factor receptor


Homologous recombination


Heat shock protein 70


Heat shock protein 90


Mitogen-activated protein kinase




Mre11, Rad50, NBS1


Maximally tolerated dose


Non-homologous end-joining


Phosphoinositide 3-kinases




Poly(ADP-ribose) polymerase


Pax2 transactivation domain-interacting protein




Conflict of Interest

No potential conflicts of interest were disclosed.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Mayo Clinic Medical Scientist Training Program, Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical SciencesMayo ClinicRochesterUSA
  2. 2.Department of Radiation OncologyUniversity of Arkansas for Medical SciencesLittle RockUSA

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