Abstract
The promise of personalized therapy for breast cancer is that therapeutic efficacy will be increased while toxic effects are reduced to a minimum. To achieve this goal, there is now an emphasis on the design of therapies that are based not only on the clinical manifestations of the disease, but also on the underlying molecular and cellular biology of cancer. However, identifying targets for personalized therapies in breast cancer is challenging. Here, we describe how biological concepts such as synthetic lethality and oncogene addiction can be used to identify new therapeutic targets and approaches. We discuss the current clinical developments in implementing synthetic lethality therapies, and highlight new ways in which this approach could be used to target specific subsets of breast cancer.
Key Points
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Biological concepts such as oncogene addiction and synthetic lethality can be used to design novel approaches to breast cancer treatment
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Preclinical work has firmly established synthetic lethality between dysfunction of the tumor suppressor genes BRCA1 and BRCA2 and inhibition of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP)
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Clinical trials in BRCA mutation carriers with breast cancer suggest that the BRCA/PARP synthetic lethality has considerable promise
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It is as yet unclear which fraction of sporadic breast cancers, if any, might respond to PARP inhibitors; trials that encompass mechanism-based biomarkers are now required
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Synthetic lethal interactions can be rapidly identified in the laboratory using high-throughput RNA interference and chemical and drug screening
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The concept of synthetic lethality could also be used to address pharmacologically intractable targets in breast cancer
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References
Beslija, S. et al. Third consensus on medical treatment of metastatic breast cancer. Ann. Oncol. 20, 1771–1785 (2009).
Paik, S. et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med. 351, 2817–2826 (2004).
Fisher, B. et al. Findings from recent National Surgical Adjuvant Breast and Bowel Project adjuvant studies in stage I breast cancer. J. Natl Cancer Inst. Monogr. 2001, 62–66 (2001).
Collins, I. & Workman, P. New approaches to molecular cancer therapeutics. Nat. Chem. Biol. 2, 689–700 (2006).
Pleasance, E. D. et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463, 191–196 (2010).
Bignell, G. R. et al. Signatures of mutation and selection in the cancer genome. Nature 463, 893–898 (2010).
Weinstein, I. B. Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297, 63–64 (2002).
Weinstein, I. B. & Joe, A. Oncogene addiction. Cancer Res. 68, 3077–3080 (2008).
Lord, C. J. & Ashworth, A. Biology-driven cancer drug development: back to the future. BMC Biol. 8, 38 (2010).
Cleator, S. J., Ahamed, E., Coombes, R. C. & Palmieri, C. A 2009 update on the treatment of patients with hormone receptor-positive breast cancer. Clin. Breast Cancer 9 (Suppl. 1), S6–S17 (2009).
Love, R. R. & Philips, J. Oophorectomy for breast cancer: history revisited. J. Natl Cancer Inst. 94, 1433–1434 (2002).
Berger, M. S. et al. Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res. 48, 1238–1243 (1988).
Vogel, C. 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. 20, 719–726 (2002).
Cobleigh, M. A. et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 17, 2639–2648 (1999).
Harries, M. & Smith, I. The development and clinical use of trastuzumab (Herceptin). Endocr. Relat. Cancer 9, 75–85 (2002).
Brandes, A. A., Franceschi, E., Tosoni, A. & Degli Esposti, R. Trastuzumab and lapatinib beyond trastuzumab progression for metastatic breast cancer: strategies and pitfalls. Expert Rev. Anticancer Ther. 10, 179–184 (2010).
Lu, Y., Zi, X., Zhao, Y., Mascarenhas, D. & Pollak, M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J. Natl Cancer Inst. 93, 1852–1857 (2001).
Sharma, S. V. & Settleman, J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 21, 3214–3231 (2007).
Konopka, J. B., Watanabe, S. M. & Witte, O. N. An alteration of the human c-abl protein in K562 leukemia cells unmasks associated tyrosine kinase activity. Cell 37, 1035–1042 (1984).
Druker, B. J. et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N. Engl. J. Med. 344, 1031–1037 (2001).
Druker, B. J. Perspectives on the development of a molecularly targeted agent. Cancer Cell 1, 31–36 (2002).
Chapman, P. et al. Early efficacy signal demonstrated in advanced melanoma in a phase I trial of the oncogenic BRAF-selective inhibitor PLX4032 [abstract]. Eur. J. Cancer Suppl. 7, 6BA (2009).
Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).
Roa, B. B., Boyd, A. A., Volcik, K. & Richards, C. S. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat. Genet. 14, 185–187 (1996).
Oddoux, C. et al. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat. Genet. 14, 188–190 (1996).
Dobzhansky, T. Genetics of natural populations. Xiii. Recombination and variability in populations of Drosophila pseudoobscura. Genetics 31, 269–290 (1946).
Lucchesi, J. C. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanogaster. Genetics 59, 37–44 (1968).
Hartwell, L. H., Szankasi, P., Roberts, C. J., Murray, A. W. & Friend, S. H. Integrating genetic approaches into the discovery of anticancer drugs. Science 278, 1064–1068 (1997).
Kaelin, W. G. Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat. Rev. Cancer 5, 689–698 (2005).
Bryant, H. E. et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434, 913–917 (2005).
Farmer, H. et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917–921 (2005).
Amé, J. C., Spenlehauer, C. & de Murcia, G. The PARP superfamily. Bioessays 26, 882–893 (2004).
Tutt, A. N. et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb. Symp. Quant. Biol. 70, 139–148 (2005).
Symington, L. S. Focus on recombinational DNA repair. EMBO Rep. 6, 512–517 (2005).
Arnaudeau, C., Lundin, C. & Helleday, T. DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells. J. Mol. Biol. 307, 1235–1245 (2001).
McCabe, N. et al. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: an issue of potency. Cancer Biol. Ther. 4, 934–936 (2005).
Edwards, S. L. et al. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111–1115 (2008).
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
Fong, P. C. et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J. Clin. Oncol. 28, 2512–2519 (2010).
Tutt, A. et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 376, 235–244 (2010).
Tutt, A. et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer [abstract]. J. Clin. Oncol. 27, CRA501 (2009).
Audeh, M. W. 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. Lancet 376, 245–251 (2010).
Turner, N., Tutt, A. & Ashworth, A. Hallmarks of 'BRCAness' in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).
Breast Cancer Linkage Consortium. Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349, 1505–1510 (1997).
Bergamaschi, A. et al. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 45, 1033–1040 (2006).
Horlings, H. M. et al. Integration of DNA copy number alterations and prognostic gene expression signatures in breast cancer patients. Clin. Cancer Res. 16, 651–663 (2010).
Turner, N. C. & Reis-Filho, J. S. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25, 5846–5853 (2006).
O'Shaughnessy, J. et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: results of a randomized phase II trial [abstract]. J. Clin. Oncol. 27, 3 (2009).
O'Shaughnessy, J. O. et al. Updated results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a PARP inhibitor, in combination with gemcitabine/carboplatin in metastatic triple-negative breast cancer [abstract]. San Antonio Breast Cancer Symposium Annual Meeting, 3122 (2009).
Chen, G. & Pan, Q. C. Potentiation of the antitumor activity of cisplatin in mice by 3-aminobenzamide and nicotinamide. Cancer Chemother. Pharmacol. 22, 303–307 (1988).
Pan, Q. C. & Guo, H. Y. The potentiation of the antitumor activity but not toxicity of bleomycin by 3-aminobenzamide. J. Antibiot. (Tokyo) 42, 1860–1868 (1989).
Zaremba, T. & Curtin, N. J. PARP inhibitor development for systemic cancer targeting. Anticancer Agents Med. Chem. 7, 515–523 (2007).
Heinemann, V. Gemcitabine plus cisplatin for the treatment of metastatic breast cancer. Clin. Breast Cancer 3 (Suppl. 1), 24–29 (2002).
Sirohi, B. et al. Platinum-based chemotherapy in triple-negative breast cancer. Ann. Oncol. 19, 1847–1852 (2008).
Gelmon, K. A. et al. Can we define tumors that will respond to PARP inhibitors? A phase II correlative study of olaparib in advanced serous ovarian cancer and triple-negative breast cancer [abstract]. J. Clin. Oncol. 28, 3002 (2010).
Salmena, L., Carracedo, A. & Pandolfi, P. P. Tenets of PTEN tumor suppression. Cell 133, 403–414 (2008).
Yin, Y. & Shen, W. H. PTEN: a new guardian of the genome. Oncogene 27, 5443–5453 (2008).
Mendes-Pereira, A. M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).
Shen, W. H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).
Gupta, A. et al. Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle 8, 2198–2210 (2009).
Graeser, M. K. et al. A marker of homologous recombination predicts pathological complete response to neoadjuvant chemotherapy in primary breast cancer. Clin. Cancer Res. doi:10.1158/1078-0432.CCR-10-1027.
Mukhopadhyay, A. et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin. Cancer Res. 16, 2344–2351 (2010).
Asakawa, H. et al. Prediction of breast cancer sensitivity to neoadjuvant chemotherapy based on status of DNA damage repair proteins. Breast Cancer Res. 12, R17 (2010).
Konstantinopoulos, P. A. et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J. Clin. Onc. 28, 3555–3561 (2010).
Sakai, W. et al. Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 69, 6381–6386 (2009).
Sakai, W. et al. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451, 1116–1120 (2008).
Swisher, E. M. et al. Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res. 68, 2581–2586 (2008).
Rottenberg, S. 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. USA 105, 17079–17084 (2008).
Gottipati, P. et al. Poly(ADP-ribose) polymerase is hyperactivated in homologous recombination-defective cells. Cancer Res. 70, 5389–5398 (2010).
Natrajan, R. et al. Tiling path genomic profiling of grade 3 invasive ductal breast cancers. Clin. Cancer Res. 15, 2711–2722 (2009).
Hynes, N. E. & Stoelzle, T. Key signalling nodes in mammary gland development and cancer: Myc. Breast Cancer Res. 11, 210 (2009).
Wang, Y. et al. Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell 5, 501–512 (2004).
Di Leva, G. & Croce, C. M. Roles of small RNAs in tumor formation. Trends Mol. Med. 16, 257–267 (2010).
Weng, L. P. et al. PTEN suppresses breast cancer cell growth by phosphatase activity-dependent G1 arrest followed by cell death. Cancer Res. 59, 5808–5814 (1999).
Baldwin, A. et al. Kinase requirements in human cells: V. Synthetic lethal interactions between p53 and the protein kinases SGK2 and PAK3. Proc. Natl Acad. Sci. USA 107, 12463–12468 (2010).
Ruzankina, Y. et al. Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53. Nat. Genet. 41, 1144–1149 (2009).
Reinhardt, H. C., Aslanian, A. S., Lees, J. A. & Yaffe, M. B. p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11, 175–189 (2007).
McCabe, N. et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 66, 8109–8115 (2006).
Williamson, C. T. et al. ATM deficiency sensitizes mantle cell lymphoma cells to poly(ADP-ribose) polymerase-1 inhibitors. Mol. Cancer Ther. 9, 347–357 (2010).
Dong, Y., Li, A., Wang, J., Weber, J. D. & Michel, L. S. Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res. 70, 5465–5474 (2010).
Bauzon, F. & Zhu, L. Racing to block tumorigenesis after pRb loss: an innocuous point mutation wins with synthetic lethality. Cell Cycle 9, 2118–2123 (2010).
Molenaar, J. J. et al. Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells. Proc. Natl Acad. Sci. USA 106, 12968–12973 (2009).
Acknowledgements
We thank members of the Gene Function Laboratory and clinical collaborators for sharing insight and/or preliminary data. Work in our laboratory is funded by Breakthrough Breast Cancer, CRUK, AACR, BCRF, The Breast Cancer Campaign and The Komen Foundation.
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A. Ashworth and C. J. Lord are patent applicants/holders in association with the Institute of Cancer Research and AstraZeneca Rewards to Inventors Scheme. F. L. Rehman declares no competing interests.
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Rehman, F., Lord, C. & Ashworth, A. Synthetic lethal approaches to breast cancer therapy. Nat Rev Clin Oncol 7, 718–724 (2010). https://doi.org/10.1038/nrclinonc.2010.172
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DOI: https://doi.org/10.1038/nrclinonc.2010.172
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