title: Sequential Combination Therapy of CDK Inhibition and Doxorubicin Is Synthetically Lethal in p53-Mutant Triple-Negative Breast Cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive malignancy in which the tumors lack expression of estrogen receptor, progesterone receptor, and HER2. Hence, TNBC patients cannot benefit from clinically available targeted therapies and rely on chemotherapy and surgery for treatment. While initially responding to chemotherapy, TNBC patients are at increased risk of developing distant metastasis and have decreased overall survival compared with non-TNBC patients. A majority of TNBC tumors carry p53 mutations, enabling them to bypass the G1 checkpoint and complete the cell cycle even in the presence of DNA damage. Therefore, we hypothesized that TNBC cells are sensitive to cell-cycle-targeted combination therapy, which leaves nontransformed cells unharmed. Our findings demonstrate that sequential administration of the pan-CDK inhibitor roscovitine before doxorubicin treatment is synthetically lethal explicitly in TNBC cells. Roscovitine treatment arrests TNBC cells in the G2-M cell-cycle phase, priming them for DNA damage. Combination treatment increased frequency of DNA double-strand breaks, while simultaneously reducing recruitment of homologous recombination proteins compared with doxorubicin treatment alone. Furthermore, this combination therapy significantly reduced tumor volume and increased overall survival compared with single drug or concomitant treatment in xenograft studies. Examination of isogenic immortalized human mammary epithelial cells and isogenic tumor cell lines found that abolishment of the p53 pathway is required for combination-induced cytotoxicity, making p53 a putative predictor of response to therapy. By exploiting the specific biologic and molecular characteristics of TNBC tumors, this innovative therapy can greatly impact the treatment and care of TNBC patients. Mol Cancer Ther; 15(4); 593-607. ©2016 AACR.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Jabbour-Leung
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tuyen
authors.initials: T
authors.lastname: Bui
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dong
authors.initials: D
authors.lastname: Yang
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Smruthi
authors.initials: S
authors.lastname: Vijayaraghavan
authors.affiliation: Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McArthur
authors.affiliation: Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. kkeyomar@mdanderson.org.
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000072020:Synthetic Lethal Mutations; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D018844:Cyclin-Dependent Kinases
references.citation: Breast Cancer Res Treat. 2005 Mar;90(1):5-14
references.pmid: 15770521
references.citation: J Virol. 1999 Sep;73(9):7297-307
references.pmid: 10438818
references.citation: Int Rev Cytol. 1980;68:251-306
references.pmid: 7014501
references.citation: Nature. 2004 Oct 21;431(7011):1011-7
references.pmid: 15496928
references.citation: Cancer Res. 1994 Apr 1;54(7):1812-7
references.pmid: 8137296
references.citation: J Clin Invest. 2011 Jul;121(7):2750-67
references.pmid: 21633166
references.citation: N Engl J Med. 2010 Nov 11;363(20):1938-48
references.pmid: 21067385
references.citation: Cancer Res. 2005 Oct 15;65(20):9320-7
references.pmid: 16230394
references.citation: J Virol. 1991 Dec;65(12):6671-6
references.pmid: 1658367
references.citation: J Clin Oncol. 2006 Apr 10;24(11):1770-83
references.pmid: 16603719
references.citation: N Engl J Med. 2002 Nov 14;347(20):1566-75
references.pmid: 12432043
references.citation: Lancet Oncol. 2007 Mar;8(3):235-44
references.pmid: 17329194
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Proc Natl Acad Sci U S A. 1990 Jan;87(1):463-7
references.pmid: 2153303
references.citation: Nat Rev Mol Cell Biol. 2003 Sep;4(9):712-20
references.pmid: 14506474
references.citation: Eur J Biochem. 1997 Jan 15;243(1-2):518-26
references.pmid: 9030780
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10640-5
references.pmid: 23754376
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Science. 1998 Nov 20;282(5393):1497-501
references.pmid: 9822382
references.citation: Expert Opin Ther Pat. 2010 Mar;20(3):377-404
references.pmid: 20180621
references.citation: Clin Cancer Res. 2002 Apr;8(4):1172-81
references.pmid: 11948130
references.citation: Cancer Res. 2008 Oct 1;68(19):7966-74
references.pmid: 18829554
references.citation: Expert Opin Investig Drugs. 2005 Apr;14(4):457-77
references.pmid: 15882121
references.citation: Am J Pathol. 2013 Oct;183(4):1064-74
references.pmid: 23920327
references.citation: J Clin Oncol. 2005 Dec 20;23(36):9408-21
references.pmid: 16361640
references.citation: Nanomedicine. 2005 Sep;1(3):193-212
references.pmid: 17292079
references.citation: Nat Rev Clin Oncol. 2015 Jan;12(1):27-41
references.pmid: 25286972
references.citation: Nat Rev Clin Oncol. 2010 Dec;7(12):683-92
references.pmid: 20877296
references.citation: Trends Pharmacol Sci. 2008 Jan;29(1):16-21
references.pmid: 18054800
references.citation: Cancer. 2007 Aug 15;110(4):876-84
references.pmid: 17620276
references.citation: Cell Cycle. 2014;13(16):2587-99
references.pmid: 25486199
references.citation: Clin Cancer Res. 2015 Apr 1;21(7):1688-98
references.pmid: 25208879
references.citation: Oncogene. 2003 Jul 31;22(31):4898-904
references.pmid: 12894232
references.citation: J Biol Chem. 2009 Apr 3;284(14):9558-65
references.pmid: 19202191
references.citation: Cancer Res. 2010 Jan 15;70(2):440-6
references.pmid: 20068163
references.citation: Cancer Treat Rev. 2013 Aug;39(5):541-50
references.pmid: 23321033
references.citation: Mol Pharm. 2011 Feb 7;8(1):185-203
references.pmid: 20942457
references.citation: Womens Health (Lond). 2007 Sep;3(5):557-69
references.pmid: 19804033
references.citation: Curr Drug Targets. 2010 Mar;11(3):279-90
references.pmid: 20210753
references.citation: Cancer. 2007 May 1;109(9):1721-8
references.pmid: 17387718
references.citation: Nat Cell Biol. 2006 Jan;8(1):37-45
references.pmid: 16327781
references.citation: Nat Rev Cancer. 2009 Mar;9(3):153-66
references.pmid: 19238148
references.citation: Clin Cancer Res. 2007 Aug 1;13(15 Pt 1):4429-34
references.pmid: 17671126
references.citation: J Biol Chem. 2008 Mar 21;283(12):7713-20
references.pmid: 18171670
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74
references.pmid: 11553815
references.citation: Breast Dis. 2010;32(1-2):35-48
references.pmid: 21778573
references.citation: Invest New Drugs. 2015 Aug;33(4):890-4
references.pmid: 25947565
references.citation: Breast Cancer Res Treat. 2012 Apr;132(2):575-88
references.pmid: 21695458
references.citation: Gene Ther. 1999 Jan;6(1):22-33
references.pmid: 10341872