Advertisement

Overcoming Resistance to PARP Inhibition

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

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.

Keywords

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

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

Notes

Conflict of Interest

No potential conflicts of interest were disclosed.

References

  1. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 5.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253(5015):49–53.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 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. 14.
    Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384(9951):1376–88.PubMedCrossRefGoogle Scholar
  15. 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.CrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Miller WR. Aromatase inhibitors: mechanism of action and role in the treatment of breast cancer. Semin Oncol. 2003;30:3–11.PubMedCrossRefGoogle Scholar
  24. 24.
    Padmanabhan N, Howell A, Rubens R. Mechanism of action of adjuvant chemotherapy in early breast cancer. Lancet. 1986;328(8504):411–4.CrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 26.
    Lewis JS, Jordan VC. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res. 2005;591(1):247–63.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.CrossRefGoogle Scholar
  34. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Homsi J, Daud AI. Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control. 2007;14(3):285–94.PubMedCrossRefGoogle Scholar
  41. 41.
    Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: what is their mechanism of action? Angiogenesis. 2010;13(1):1–14.PubMedCrossRefGoogle Scholar
  42. 42.
    Ellis LM. Mechanisms of action of bevacizumab as a component of therapy for metastatic colorectal cancer. Semin Oncol. 2006;33:S1–7.PubMedCrossRefGoogle Scholar
  43. 43.
    Kazazi-Hyseni F, Beijnen JH, Schellens JHM. Bevacizumab. Oncologist. 2010;15(8):819–25.  https://doi.org/10.1634/theoncologist.2009-0317.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Ciombor KK, Berlin J. Aflibercept—a decoy VEGF receptor. Curr Oncol Rep. 2014;16(2):368.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 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.CrossRefGoogle Scholar
  47. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG. PARP inhibition: PARP1 and beyond. Nat Rev Cancer. 2010;10(4):293.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Underhill C, Toulmonde M, Bonnefoi H. A review of PARP inhibitors: from bench to bedside. Ann Oncol. 2010;22(2):268–79.PubMedCrossRefGoogle Scholar
  53. 53.
    Curtin NJ. PARP inhibitors for cancer therapy. Expert Rev Mol Med. 2005;7(4):1–20.PubMedCrossRefGoogle Scholar
  54. 54.
    Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16:110.  https://doi.org/10.1038/nrc.2015.21.PubMedCrossRefGoogle Scholar
  55. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Brown JS, Kaye SB, Yap TA. PARP inhibitors: the race is on. Br J Cancer. 2016;114:713–5.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 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.CrossRefGoogle Scholar
  61. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar
  63. 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.PubMedCrossRefGoogle Scholar
  64. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 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.PubMedCrossRefGoogle Scholar
  70. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 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.PubMedCrossRefGoogle Scholar
  72. 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.PubMedCrossRefGoogle Scholar
  73. 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.PubMedCrossRefGoogle Scholar
  74. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Island BC. BRCA1 CpG island hypermethylation predicts sensitivity to poly (adenosine diphosphate)-ribose polymerase inhibitors. J Clin Oncol. 2010;28(29):e563–e4.CrossRefGoogle Scholar
  77. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 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. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 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.PubMedCrossRefGoogle Scholar
  85. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 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.PubMedCrossRefGoogle Scholar
  87. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 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.PubMedCrossRefGoogle Scholar
  89. 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.PubMedCrossRefGoogle Scholar
  90. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 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.CrossRefGoogle Scholar
  92. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 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.PubMedCrossRefGoogle Scholar
  98. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474(7353):609–15.  https://doi.org/10.1038/nature10166.CrossRefGoogle Scholar
  103. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 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.PubMedCrossRefGoogle Scholar
  105. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 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.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© 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

Personalised recommendations