Loss of 53 BP 1 causes PARP inhibitor resistance in BRCA 1-mutated mouse mammary tumors

Inhibition of poly(ADP-ribose) polymerase (PARP) is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases this is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors. Statement of significance In this study we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1deficient tumors to PARP inhibitors. Loss of 53BP1 causes PARP inhibitor resistance in BRCA1-mutated mouse mammary tumors 15

[1]  F. Couch,et al.  Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers , 2008, Nature.

[2]  S. Ganesan,et al.  Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. , 2001, Molecular cell.

[3]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[4]  L. Rubinstein,et al.  Preclinical Modeling of a Phase 0 Clinical Trial: Qualification of a Pharmacodynamic Assay of Poly (ADP-Ribose) Polymerase in Tumor Biopsies of Mouse Xenografts , 2008, Clinical Cancer Research.

[5]  Stephen P. Jackson,et al.  Human CtIP Mediates Cell Cycle Control of DNA End Resection and Double Strand Break Repair*S⃞ , 2009, Journal of Biological Chemistry.

[6]  F. Gergely,et al.  BRCA1-independent ubiquitination of FANCD2. , 2003, Molecular cell.

[7]  J. Troge,et al.  Tumour evolution inferred by single-cell sequencing , 2011, Nature.

[8]  Hong Wu,et al.  A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. , 2012, Cancer cell.

[9]  Jorge S. Reis-Filho,et al.  Resistance to therapy caused by intragenic deletion in BRCA2 , 2008, Nature.

[10]  Alan Ashworth,et al.  Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. , 2006, Cancer research.

[11]  A. Lau,et al.  4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. , 2008, Journal of medicinal chemistry.

[12]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[13]  D. Matei,et al.  Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  B. Karlan,et al.  Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. , 2008, Cancer research.

[15]  T. Ludwig,et al.  BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. , 2012, Molecular cell.

[16]  A. Lau,et al.  Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. , 2009, Cancer research.

[17]  Jos Jonkers,et al.  Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer , 2007, Proceedings of the National Academy of Sciences.

[18]  H. Gaylord,et al.  AMERICAN ASSOCIATION FOR CANCER RESEARCH. , 1913, California state journal of medicine.

[19]  P. Borst,et al.  High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs , 2008, Proceedings of the National Academy of Sciences.

[20]  D. Adams,et al.  A High-Throughput Pharmaceutical Screen Identifies Compounds with Specific Toxicity against BRCA2-Deficient Tumors , 2009, Clinical Cancer Research.

[21]  P. Borst,et al.  Cancer drug pan-resistance: pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? , 2012, Open Biology.

[22]  Peter Bouwman,et al.  BRCA1 RING function is essential for tumor suppression but dispensable for therapy resistance. , 2011, Cancer cell.

[23]  D. Adams,et al.  53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers , 2010, Nature Structural &Molecular Biology.

[24]  Maximina H. Yun,et al.  CtIP-BRCA1 modulates the choice of DNA double-strand break repair pathway throughout the cell cycle , 2009, Nature.

[25]  Rochelle L. Garcia,et al.  Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  A. Tutt,et al.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial , 2010, The Lancet.

[27]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[28]  Thomas Helleday,et al.  The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings , 2011, Molecular oncology.

[29]  J. Peterse,et al.  Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer , 2007, Proceedings of the National Academy of Sciences.

[30]  Disposition and Drug-Drug Interaction Potential of Veliparib (ABT-888), a Novel and Potent Inhibitor of Poly(ADP-ribose) Polymerase , 2011, Drug Metabolism and Disposition.

[31]  J. H. Beijnen,et al.  Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs , 1994, Cell.

[32]  P. Borst,et al.  Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[33]  S. Jackson,et al.  CDK targets Sae2 to control DNA-end resection and homologous recombination , 2008, Nature.

[34]  A. Ashworth,et al.  Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. , 2009, The New England journal of medicine.

[35]  Scott H. Kaufmann,et al.  Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells , 2011, Proceedings of the National Academy of Sciences.

[36]  Jeremy M. Stark,et al.  53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks , 2010, Cell.

[37]  M. Pajic,et al.  Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. , 2010, Cancer research.

[38]  K. A. Gelmon.  Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial , 2011 .

[39]  J. Settleman,et al.  EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer , 2010, Oncogene.