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Overcoming Resistance to PARP Inhibition

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Current Applications for Overcoming Resistance to Targeted Therapies

Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 20))

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Abstract

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.

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Abbreviations

5-FU:

5-Fluorouracil

AKT:

Protein kinase B

BARD1:

BRCA1-associated RING domain

BET:

Bromodomain and extra-terminal

BRCA1:

Breast cancer gene 1

BRCA2:

Breast cancer gene 2

CDK12:

Cyclin-dependent kinase 12

CTIP:

C-terminal binding protein interacting protein

FDA:

Food and Drug Administration

HER2:

Human epidermal growth factor receptor 2

HGFR:

Hepatocyte growth factor receptor

HR:

Homologous recombination

HSP70:

Heat shock protein 70

HSP90:

Heat shock protein 90

MAPK:

Mitogen-activated protein kinase

MDR:

Multidrug-resistant

MRN:

Mre11, Rad50, NBS1

MTD:

Maximally tolerated dose

NHEJ:

Non-homologous end-joining

P13K:

Phosphoinositide 3-kinases

PAR:

Poly(ADP-ribose)

PARP:

Poly(ADP-ribose) polymerase

PTIP:

Pax2 transactivation domain-interacting protein

Rb:

Retinoblastoma

References

  1. Roy R, Chun J, Powell SN. BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer. 2011;12:68. https://doi.org/10.1038/nrc3181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rebecca SL, Kimberly MD, Ahmedin J. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30. https://doi.org/10.3322/caac.21442.

    Article  Google Scholar 

  3. Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkäs K, Roberts J, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497–506.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Meijers-Heijboer H, van Geel B, van Putten WL, Henzen-Logmans SC, Seynaeve C, Menke-Pluymers MB, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2001;345(3):159–64.

    Article  CAS  PubMed  Google Scholar 

  5. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253(5015):49–53.

    Article  CAS  PubMed  Google Scholar 

  6. Lakhani SR, Van De Vijver MJ, Jacquemier J, Anderson TJ, Osin PP, McGuffog L, et al. The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol. 2002;20(9):2310–8.

    Article  CAS  PubMed  Google Scholar 

  7. Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233–8.

    Article  CAS  PubMed  Google Scholar 

  8. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, et al. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006;38(8):873.

    Article  CAS  PubMed  Google Scholar 

  9. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534(7605):47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304.

    Article  CAS  PubMed  Google Scholar 

  11. Patch A-M, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S, et al. Whole–genome characterization of chemoresistant ovarian cancer. Nature. 2015;521(7553):489.

    Article  CAS  PubMed  Google Scholar 

  12. Song H, Dicks SJR, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015;33(26):2901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ramus SJ, Song H, Dicks E, Tyrer JP, Rosenthal AN, Intermaggio MP, et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107(11).

    Google Scholar 

  14. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384(9951):1376–88.

    Article  PubMed  Google Scholar 

  15. Daly MB, Pilarski R, Axilbund JE, Berry M, Buys SS, Crawford B, et al. Genetic/familial high-risk assessment: breast and ovarian, version 2.2015. J Natl Compr Cancer Netw. 2016;14(2):153–62.

    Article  Google Scholar 

  16. McConechy MK, Ding J, Senz J, Yang W, Melnyk N, Tone AA, et al. Ovarian and endometrial endometrioid carcinomas have distinct CTNNB1 and PTEN mutation profiles. Mod Pathol. 2014;27(1):128.

    Article  CAS  PubMed  Google Scholar 

  17. Robson M, Im S-A, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33.

    Article  CAS  PubMed  Google Scholar 

  18. Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13(1):188. https://doi.org/10.1186/s12916-015-0425-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cortez AJ, Tudrej P, Kujawa KA, Lisowska KM. Advances in ovarian cancer therapy. Cancer Chemother Pharmacol. 2018;81(1):17–38. https://doi.org/10.1007/s00280-017-3501-8.

    Article  CAS  PubMed  Google Scholar 

  20. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154–64. https://doi.org/10.1056/NEJMoa1611310.

    Article  CAS  PubMed  Google Scholar 

  21. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43. https://doi.org/10.1056/NEJMoa052985.

    Article  CAS  PubMed  Google Scholar 

  22. Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473–83. https://doi.org/10.1056/NEJMoa1104390.

    Article  CAS  PubMed  Google Scholar 

  23. Miller WR. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin Oncol. 2003;30:3–11.

    Article  CAS  PubMed  Google Scholar 

  24. Padmanabhan N, Howell A, Rubens R. Mechanism of action of adjuvant chemotherapy in early breast cancer. Lancet. 1986;328(8504):411–4.

    Article  Google Scholar 

  25. Bryant HU. Mechanism of action and preclinical profile of raloxifene, a selective estrogen receptor modulator. Rev Endocr Metab Disord. 2001;2(1):129–38.

    Article  CAS  PubMed  Google Scholar 

  26. Lewis JS, Jordan VC. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res. 2005;591(1):247–63.

    Article  CAS  PubMed  Google Scholar 

  27. Jordan V, Dix C, Rowsby L, Prestwich G. Studies on the mechanism of action of the nonsteroidal antioestrogen tamoxifen (ICI 46,474) in the rat. Mol Cell Endocrinol. 1977;7(2):177–92.

    Article  CAS  PubMed  Google Scholar 

  28. Sawka CA, Pritchard KI, Paterson AH, Sutherland DJ, Thomson DB, Shelley WE, et al. Role and mechanism of action of tamoxifen in premenopausal women with metastatic breast carcinoma. Cancer Res. 1986;46(6):3152–6.

    CAS  PubMed  Google Scholar 

  29. Osborne C, Wakeling A, Nicholson R. Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer. 2004;90(S1):S2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793):771–84. https://doi.org/10.1016/s0140-6736(11)60993-8.

    Article  CAS  PubMed  Google Scholar 

  31. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719–26.

    Article  CAS  PubMed  Google Scholar 

  32. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84.

    Article  CAS  PubMed  Google Scholar 

  33. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659–72.

    Article  CAS  PubMed  Google Scholar 

  34. O’Sullivan CC, Ruddy KJ. Management of potential long-term toxicities in breast cancer patients. Curr Breast Cancer Rep. 2016;8(4):183–92. https://doi.org/10.1007/s12609-016-0229-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nowsheen S, Viscuse PV, O'Sullivan CC, Sandhu NP, Haddad TC, Blaes A, et al. Incidence, diagnosis, and treatment of cardiac toxicity from trastuzumab in patients with breast cancer. Curr Breast Cancer Rep. 2017;9(3):173–82. https://doi.org/10.1007/s12609-017-0249-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nowsheen S, Duma N, Ruddy KJ. Preventing today’s survivors of breast cancer from becoming tomorrow's cardiac patients. J Oncol Pract. 2018;14(4):213–4. https://doi.org/10.1200/JOP.18.00130.

    Article  PubMed  Google Scholar 

  37. Yu Q, Sicinska E, Geng Y, Ahnström M, Zagozdzon A, Kong Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006;9(1):23–32.

    Article  CAS  PubMed  Google Scholar 

  38. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875–84.

    Article  CAS  PubMed  Google Scholar 

  39. Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, et al. MONARCH 1, a phase II study of Abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2− metastatic breast cancer. Clin Cancer Res. 2017;23(17):5218–24. https://doi.org/10.1158/1078-0432.ccr-17-0754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Homsi J, Daud AI. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control. 2007;14(3):285–94.

    Article  PubMed  Google Scholar 

  41. Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14.

    Article  CAS  PubMed  Google Scholar 

  42. Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol. 2006;33:S1–7.

    Article  CAS  PubMed  Google Scholar 

  43. Kazazi-Hyseni F, Beijnen JH, Schellens JHM. Bevacizumab. Oncologist. 2010;15(8):819–25. https://doi.org/10.1634/theoncologist.2009-0317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Oza AM, Cook AD, Pfisterer J, Embleton A, Ledermann JA, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): overall survival results of a phase 3 randomised trial. Lancet Oncol. 2015;16(8):928–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ciombor KK, Berlin J. Aflibercept—a decoy VEGF receptor. Curr Oncol Rep. 2014;16(2):368.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Benson AB, Bekaii-Saab T, Chan E, Chen Y-J, Choti MA, Cooper HS, et al. Metastatic colon cancer, version 3.2013 featured updates to the NCCN guidelines. J Natl Compr Cancer Netw. 2013;11(2):141–52.

    Article  CAS  Google Scholar 

  47. Fan W, Chang J, Fu P. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Future Med Chem. 2015;7(12):1511–9. https://doi.org/10.4155/fmc.15.93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Luque-Cabal M, García-Teijido P, Fernández-Pérez Y, Sánchez-Lorenzo L, Palacio-Vázquez I. Mechanisms behind the resistance to Trastuzumab in HER2-amplified breast cancer and strategies to overcome it. Clin Med Insights Oncol. 2016;10(Suppl 1):21–30. https://doi.org/10.4137/CMO.S34537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3(1):39–55. https://doi.org/10.1016/j.trecan.2016.11.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Loges S, Schmidt T, Carmeliet P. Mechanisms of resistance to anti-angiogenic therapy and development of third-generation anti-angiogenic drug candidates. Genes Cancer. 2010;1(1):12–25. https://doi.org/10.1177/1947601909356574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Underhill C, Toulmonde M, Bonnefoi H. A review of PARP inhibitors: from bench to bedside. Ann Oncol. 2010;22(2):268–79.

    Article  PubMed  Google Scholar 

  53. Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med. 2005;7(4):1–20.

    Article  PubMed  Google Scholar 

  54. Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110. https://doi.org/10.1038/nrc.2015.21.

    Article  CAS  PubMed  Google Scholar 

  55. Murai J, Shar-yin NH, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brown JS, Kaye SB, Yap TA. PARP inhibitors: the race is on. Br J Cancer. 2016;114:713–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Yap TA, Sandhu SK, Carden CP, de Bono JS. Poly (ADP-Ribose) polymerase (PARP) inhibitors: exploiting a synthetic lethal strategy in the clinic. CA Cancer J Clin. 2011;61(1):31–49.

    Article  PubMed  Google Scholar 

  58. Brown JS, O’Carrigan B, Jackson SP, Yap TA. Targeting DNA repair in cancer: beyond PARP inhibitors. Cancer Discov. 2017;7(1):20–37.

    Article  CAS  PubMed  Google Scholar 

  59. Ibrahim YH, García-García C, Serra V, He L, Torres-Lockhart K, Prat A, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov. 2012;2(11):1036–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. O’Shaughnessy J, Osborne C, Pippen J, Yoffe M, Patt D, Monaghan G, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol. 2009;27(18S):3.

    Article  Google Scholar 

  61. Ossovskaya V, Koo IC, Kaldjian EP, Alvares C, Sherman BM. Upregulation of poly (ADP-ribose) polymerase-1 (PARP1) in triple-negative breast cancer and other primary human tumor types. Genes Cancer. 2010;1(8):812–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382–92.

    Article  CAS  PubMed  Google Scholar 

  63. Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(9):1274–84.

    Article  CAS  PubMed  Google Scholar 

  64. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 2017;18(1):75–87.

    Article  CAS  PubMed  Google Scholar 

  66. Sizemore ST, Mohammed R, Sizemore GM, Nowsheen S, Yu H, Ostrowski MC, et al. Synthetic lethality of PARP inhibition and ionizing radiation is p53-dependent. Mol Cancer Res. 2018;16:1092–102. https://doi.org/10.1158/1541-7786.MCR-18-0106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wiltshire TD, Lovejoy CA, Wang T, Xia F, O'Connor MJ, Cortez D. Sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition identifies ubiquitin-specific peptidase 11 (USP11) as a regulator of DNA double-strand break repair. J Biol Chem. 2010;285(19):14565–71. https://doi.org/10.1074/jbc.M110.104745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang H, Yang ES, Jiang J, Nowsheen S, Xia F. DNA damage-induced cytotoxicity is dissociated from BRCA1’s DNA repair function but is dependent on its cytosolic accumulation. Cancer Res. 2010;70(15):6258–67. https://doi.org/10.1158/0008-5472.can-09-4713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Jiang J, Yang ES, Jiang G, Nowsheen S, Wang H, Wang T, et al. p53-dependent BRCA1 nuclear export controls cellular susceptibility to DNA damage. Cancer Res. 2011;71(16):5546–57. https://doi.org/10.1158/0008-5472.can-10-3423.

    Article  CAS  PubMed  Google Scholar 

  70. Yang ES, Nowsheen S, Rahman MA, Cook RS, Xia F. Targeting BRCA1 localization to augment breast tumor sensitivity to poly(ADP-Ribose) polymerase inhibition. Cancer Res. 2012;72(21):5547–55. https://doi.org/10.1158/0008-5472.can-12-0934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Feng Z, Kachnic L, Zhang J, Powell SN, Xia F. DNA damage induces p53-dependent BRCA1 nuclear export. J Biol Chem. 2004;279(27):28574–84. https://doi.org/10.1074/jbc.M404137200.

    Article  CAS  PubMed  Google Scholar 

  72. Xia F, Powell SN. The molecular basis of radiosensitivity and chemosensitivity in the treatment of breast cancer. Semin Radiat Oncol. 2002;12(4):296–304. https://doi.org/10.1053/srao.2002.35250.

    Article  PubMed  Google Scholar 

  73. Barber LJ, Sandhu S, Chen L, Campbell J, Kozarewa I, Fenwick K, et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol. 2013;229(3):422–9. https://doi.org/10.1002/path.4140.

    Article  CAS  PubMed  Google Scholar 

  74. Norquist B, Wurz KA, Pennil CC, Garcia R, Gross J, Sakai W, et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol. 2011;29(22):3008–15. https://doi.org/10.1200/JCO.2010.34.2980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kondrashova O, Nguyen M, Shield-Artin K, Tinker AV, Teng NNH, Harrell MI, et al. Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor Rucaparib in high-grade ovarian carcinoma. Cancer Discov. 2017;7(9):984–98. https://doi.org/10.1158/2159-8290.CD-17-0419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Island BC. BRCA1 CpG island hypermethylation predicts sensitivity to poly (adenosine diphosphate)-ribose polymerase inhibitors. J Clin Oncol. 2010;28(29):e563–e4.

    Article  Google Scholar 

  77. Jacot W, Thezenas S, Senal R, Viglianti C, Laberenne A-C, Lopez-Crapez E, et al. BRCA1 promoter hypermethylation, 53BP1 protein expression and PARP-1 activity as biomarkers of DNA repair deficit in breast cancer. BMC Cancer. 2013;13(1):523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Yang L, Zhang Y, Shan W, Hu Z, Yuan J, Pi J, et al. Repression of BET activity sensitizes homologous recombination–proficient cancers to PARP inhibition. Sci Transl Med. 2017;9(400):eaal1645.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Karakashev S, Zhu H, Yokoyama Y, Zhao B, Fatkhutdinov N, Kossenkov AV, et al. BET bromodomain inhibition synergizes with PARP inhibitor in epithelial ovarian cancer. Cell Rep. 2017;21(12):3398–405. https://doi.org/10.1016/j.celrep.2017.11.095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Sun C, Yin J, Fang Y, Chen J, Jeong KJ, Chen X, et al. BRD4 inhibition is synthetic lethal with PARP inhibitors through the induction of homologous recombination deficiency. Cancer Cell. 2018;33(3):401–16.e8. https://doi.org/10.1016/j.ccell.2018.01.019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sun C, Fang Y, Yin J, Chen J, Ju Z, Zhang D, et al. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers. Sci Transl Med. 2017:9.

    Google Scholar 

  82. Pettitt SJ, Krastev DB, Brandsma I, Dréan A, Song F, Aleksandrov R, et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun. 2018;9(1):1849. https://doi.org/10.1038/s41467-018-03917-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141(2):243–54. https://doi.org/10.1016/j.cell.2010.03.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013;3(1):68–81. https://doi.org/10.1158/2159-8290.CD-12-0049.

    Article  CAS  PubMed  Google Scholar 

  85. Xu G, Chapman JR, Brandsma I, Yuan J, Mistrik M, Bouwman P, et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature. 2015;521(7553):541–4. https://doi.org/10.1038/nature14328.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M, et al. DNA repair network analysis reveals Shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell. 2018;173(4):972–88.e23. https://doi.org/10.1016/j.cell.2018.03.050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Johnson N, Johnson SF, Yao W, Li YC, Choi YE, Bernhardy AJ, et al. Stabilization of mutant BRCA1 protein confers PARP inhibitor and platinum resistance. Proc Natl Acad Sci U S A. 2013;110(42):17041–6. https://doi.org/10.1073/pnas.1305170110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ray Chaudhuri A, Callen E, Ding X, Gogola E, Duarte AA, Lee JE, et al. Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature. 2016;535(7612):382–7. https://doi.org/10.1038/nature18325.

    Article  CAS  PubMed  Google Scholar 

  89. Patel AG, Flatten KS, Schneider PA, Dai NT, McDonald JS, Poirier GG, et al. Enhanced killing of cancer cells by poly (ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes. J Biol Chem. 2012;287(6):4198–210.

    Article  CAS  PubMed  Google Scholar 

  90. Znojek P, Willmore E, Curtin NJ. Preferential potentiation of topoisomerase I poison cytotoxicity by PARP inhibition in S phase. Br J Cancer. 2014;111(7):1319–26. https://doi.org/10.1038/bjc.2014.378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A, et al. Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Investig New Drugs. 2012;30(4):1493–500. https://doi.org/10.1007/s10637-011-9682-9.

    Article  CAS  Google Scholar 

  92. Johnson SF, Cruz C, Greifenberg AK, Dust S, Stover DG, Chi D, et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep. 2016;17(9):2367–81. https://doi.org/10.1016/j.celrep.2016.10.077.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Garcia TB, Snedeker JC, Baturin D, Gardner L, Fosmire SP, Zhou C, et al. A small-molecule inhibitor of WEE1, AZD1775, synergizes with Olaparib by impairing homologous recombination and enhancing DNA damage and apoptosis in acute leukemia. Mol Cancer Ther. 2017;16(10):2058–68. https://doi.org/10.1158/1535-7163.MCT-16-0660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, et al. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008;105(44):17079–84. https://doi.org/10.1073/pnas.0806092105.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Kievit FM, Wang FY, Fang C, Mok H, Wang K, Silber JR, et al. Doxorubicin loaded iron oxide nanoparticles overcome multidrug resistance in cancer in vitro. J Control Release. 2011;152(1):76–83. https://doi.org/10.1016/j.jconrel.2011.01.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Batrakova EV, Kabanov AV. Pluronic block copolymers: evolution of drug delivery concept from inert nanocarriers to biological response modifiers. J Control Release. 2008;130(2):98–106. https://doi.org/10.1016/j.jconrel.2008.04.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Chen Y, Zhang W, Gu J, Ren Q, Fan Z, Zhong W, et al. Enhanced antitumor efficacy by methotrexate conjugated pluronic mixed micelles against KBv multidrug resistant cancer. Int J Pharm. 2013;452(1–2):421–33. https://doi.org/10.1016/j.ijpharm.2013.05.015.

    Article  CAS  PubMed  Google Scholar 

  98. Patel NR, Rathi A, Mongayt D, Torchilin VP. Reversal of multidrug resistance by co-delivery of tariquidar (XR9576) and paclitaxel using long-circulating liposomes. Int J Pharm. 2011;416(1):296–9. https://doi.org/10.1016/j.ijpharm.2011.05.082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Meng H, Mai WX, Zhang H, Xue M, Xia T, Lin S, et al. Codelivery of an optimal drug/siRNA combination using mesoporous silica nanoparticles to overcome drug resistance in breast cancer in vitro and in vivo. ACS Nano. 2013;7(2):994–1005. https://doi.org/10.1021/nn3044066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Amiri-Kordestani L, Basseville A, Kurdziel K, Fojo AT, Bates SE. Targeting MDR in breast and lung cancer: discriminating its potential importance from the failure of drug resistance reversal studies. Drug Resist Updat. 2012;15(1–2):50–61. https://doi.org/10.1016/j.drup.2012.02.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Du Y, Yamaguchi H, Wei Y, Hsu JL, Wang HL, Hsu YH, et al. Blocking c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors. Nat Med. 2016;22(2):194–201. https://doi.org/10.1038/nm.4032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15. https://doi.org/10.1038/nature10166.

    Article  CAS  Google Scholar 

  103. Choi YE, Meghani K, Brault M-E, Leclerc L, He YJ, Day TA, et al. Platinum and PARP inhibitor resistance due to overexpression of microRNA-622 in BRCA1-mutant ovarian cancer. Cell Rep. 2016;14(3):429–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Moskwa P, Buffa FM, Pan Y, Panchakshari R, Gottipati P, Muschel RJ, et al. miR-182-mediated downregulation of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors. Mol Cell. 2011;41(2):210–20.

    Article  CAS  PubMed  Google Scholar 

  105. Byers LA, Wang J, Nilsson MB, Fujimoto J, Saintigny P, Yordy J, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discov. 2012;2(9):798–811. https://doi.org/10.1158/2159-8290.CD-12-0112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res. 2012;72(21):5588–99. https://doi.org/10.1158/0008-5472.CAN-12-2753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703. https://doi.org/10.1038/nm.4333.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Yates LR, Knappskog S, Wedge D, Farmery JH, Gonzalez S, Martincorena I, et al. Genomic evolution of breast cancer metastasis and relapse. Cancer Cell. 2017;32(2):169–84.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Mayo Clinic Medical Scientist Training Program, Mayo Clinic Alix School of Medicine and Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN, USA

    Somaira Nowsheen

  2. Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Fen Xia

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  1. Somaira Nowsheen
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  2. Fen Xia
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Correspondence to Fen Xia .

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  1. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Myron R. Szewczuk

  2. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Bessi Qorri

  3. Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada

    Manpreet Sambi

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Nowsheen, S., Xia, F. (2019). Overcoming Resistance to PARP Inhibition. In: Szewczuk, M., Qorri, B., Sambi, M. (eds) Current Applications for Overcoming Resistance to Targeted Therapies. Resistance to Targeted Anti-Cancer Therapeutics, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-21477-7_6

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