Combined inhibition of DDR1 and CDK4/6 induces synergistic effects in ER-positive, HER2-negative breast cancer with PIK3CA/AKT1 mutations.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ drug therapy
Cell Cycle Checkpoints
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Class I Phosphatidylinositol 3-Kinases
/ genetics
Cyclin-Dependent Kinases
/ antagonists & inhibitors
Discoidin Domain Receptor 1
/ antagonists & inhibitors
Female
Humans
MCF-7 Cells
Mutation
/ genetics
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-akt
/ genetics
Receptor, ErbB-2
/ genetics
Receptors, Estrogen
/ genetics
Signal Transduction
/ drug effects
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
10
11
2020
accepted:
23
04
2021
revised:
09
04
2021
pubmed:
11
6
2021
medline:
22
12
2021
entrez:
10
6
2021
Statut:
ppublish
Résumé
Molecular alterations in the PI3K/AKT pathway occur frequently in hormone receptor-positive breast tumors. Patients with ER-positive, HER2-negative metastatic breast cancer are often treated with CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy. Although this is an effective regimen, most patients ultimately progress. The purpose of this study was identifying synthetic lethality partners that can enhance palbociclib's antitumor efficacy in the presence of PIK3CA/AKT1 mutations. We utilized a barcoded shRNA library to determine critical targets for survival in isogenic MCF7 cells with PIK3CA/AKT1 mutations. We demonstrated that the efficacy of palbociclib is reduced in the presence of PIK3CA/AKT1 mutations. We also identified that the downregulation of discoidin domain receptor 1 (DDR1) is synthetically lethal with palbociclib. DDR1 knockdown and DDR1 pharmacological inhibitor decreased cell growth and inhibited cell cycle progression in all cell lines, while enhanced the sensitivity of PIK3CA/AKT1 mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest in PIK3CA/AKT1 mutant cell lines. In vivo, 7rh significantly enhanced palbociclib's antitumor efficacy. Our data indicates that DDR1 inhibition can augment cell cycle suppressive effect of palbociclib and could be effective strategy for targeted therapy of ER-positive, HER2-negative breast cancers with PI3K pathway activation.
Identifiants
pubmed: 34108622
doi: 10.1038/s41388-021-01819-0
pii: 10.1038/s41388-021-01819-0
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Receptors, Estrogen
0
Class I Phosphatidylinositol 3-Kinases
EC 2.7.1.137
PIK3CA protein, human
EC 2.7.1.137
DDR1 protein, human
EC 2.7.10.1
Discoidin Domain Receptor 1
EC 2.7.10.1
Receptor, ErbB-2
EC 2.7.10.1
AKT1 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Cyclin-Dependent Kinases
EC 2.7.11.22
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4425-4439Subventions
Organisme : UTHealth | Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston (Center for Clinical and Translational Sciences)
ID : 1UL1TR003167-01
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : CA-16672
Références
Polyak K. Heterogeneity in breast cancer. J Clin Investig. 2011;121:3786–8.
doi: 10.1172/JCI60534
Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7.
doi: 10.1126/science.296.5573.1655
Miller TW, Rexer BN, Garrett JT, Arteaga CL. Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res. 2011;13:224
doi: 10.1186/bcr3039
Meric-Bernstam F, Zheng X, Shariati M, Damodaran S, Wathoo C, Brusco L, et al. Survival outcomes by TP53 mutation status in metastatic breast cancer. JCO Precis Oncol. 2018; 2: PO.17.00245.
Shariati M, Meric-Bernstam F. Targeting AKT for cancer therapy. Expert Opin Investig Drugs. 2019;1–12.
Andre F, Ciruelos EM, Rubovszky G, Campone M, Loibl S, Rugo HS. et al. Alpelisib (ALP) 1 fulvestrant (FUL) for advanced breast cancer (ABC): results of the phase III SOLAR-1 trial. Ann Oncol. 2018;29:709.
doi: 10.1093/annonc/mdy424.010
Hyman DM, Smyth LM, Donoghue MTA, Westin SN, Bedard PL, Dean EJ. et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35:2251–9.
doi: 10.1200/JCO.2017.73.0143
Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11:5.
doi: 10.1186/bcr2419
Toogood PL, Harvey PJ, Repine JT, Sheehan DJ, VanderWel SN, Zhou HR. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J Medicinal Chem. 2005;48:2388–406.
doi: 10.1021/jm049354h
Wander SA, Cohen O, Gong XQ, Johnson GN, Buendia-Buendia J, Lloyd M, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in patients with hormone receptor-positive (HR+)/HER2-metastatic breast cancer (MBC). Cancer Res. 2020;80:4.
Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Research. 2016;76:5907.
Jansen VM, Bhola NE, Bauer JA, Formisano L, Lee KM, Hutchinson KE. et al. Kinome-Wide RNA Interference Screen Reveals a Role for PDK1 in Acquired Resistance to CDK4/6 Inhibition in ER-Positive Breast Cancer. Cancer Res. 2017;77:2488–99.
doi: 10.1158/0008-5472.CAN-16-2653
Cortes J, Im SA, Holgado E, Perez-Garcia JM, Schmid P, Chavez-MacGregor M. The next era of treatment for hormone receptor-positive, HER2-negative advanced breast cancer: triplet combination-based endocrine therapies. Cancer Treat Rev. 2017;61:53–60.
doi: 10.1016/j.ctrv.2017.09.011
Juric D, Ismail-Khan R, Campone M, Estevez Garcia L, Becerra C, Boer R. et al. Abstract P3-14-01: phase Ib/II study of ribociclib and alpelisib and letrozole in ER+, HER2– breast cancer: safety, preliminary efficacy and molecular analysis. Cancer Res. 2016;76:P3–14.
doi: 10.1158/0008-5472.CAN-15-3239
Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C. et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26:136–49.
doi: 10.1016/j.ccr.2014.05.020
Gadiya M, Chakraborty G. Signaling by discoidin domain receptor 1 in cancer metastasis. Cell Adh Migr. 2018;12:315–23.
pubmed: 30187813
pmcid: 6363035
Belfiore A, Malaguarnera R, Nicolosi ML, Lappano R, Ragusa M, Morrione A. et al. A novel functional crosstalk between DDR1 and the IGF axis and its relevance for breast cancer. Cell Adh Migration. 2018;12:305–14.
Beaver JA, Gustin JP, Yi KH, Rajpurohit A, Thomas M, Gilbert SF. et al. PIK3CA and AKT1 Mutations Have Distinct Effects on Sensitivity to Targeted Pathway Inhibitors in an Isogenic Luminal Breast Cancer Model System. Clin Cancer Res. 2013;19:5413–22.
doi: 10.1158/1078-0432.CCR-13-0884
Palbociclib package insert [PDF on the Internet]:2016 [cited 2020 March 2]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/207103s002lbl.pdf .
Day PJ, Cleasby A, Tickle IJ, O’Reilly M, Coyle JE, Holding FP. et al. Crystal structure of human CDK4 in complex with a D-type cyclin. Proc Natl Acad Sci U.S.A. 2009;106:4166–70.
doi: 10.1073/pnas.0809645106
Moon A, Koh M, Woo Y, Lee D, Valiathan R, Jung HY.et al. Discoidin domain receptor (DDR) 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-ras-induced epithelial to mesenchymal transition. Faseb J. 2015;136:E508–E520..
Saby C, Collin G, Sinane M, Buache E, Van Gulick L, Saltel F, et al. DDR1 and MT1-MMP expression levels are determinant for triggering BIK-mediated apoptosis by 3D type I collagen matrix in invasive basal-like breast carcinoma cells. Front Pharmacol. 2019. 10;462.
Assent D, Bourgot I, Hennuy B, Geurts P, Noel A, Foidart JM, et al. A membrane-type-1 matrix metalloproteinase (MT1-MMP) - discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells. Plos ONE. 2015;10:3.
doi: 10.1371/journal.pone.0116006
Mata R, Palladino C, Nicolosi ML, Lo Presti AR, Malaguarnera R, Ragusa M. et al. IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway. Oncotarget. 2016;7:7683–7700.
doi: 10.18632/oncotarget.6524
Gao M, Duan L, Luo J, Zhang L, Lu X, Zhang Y. et al. Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J Med Chem. 2013;56:3281–95.
doi: 10.1021/jm301824k
Anders L, Ke N, Hydbring P, Choi YJ, Widlund HR, Chick JM. et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell. 2011;20:620–34.
doi: 10.1016/j.ccr.2011.10.001
Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010;29:4018–32.
doi: 10.1038/onc.2010.154
Franco J, Witkiewicz AK, Knudsen ES. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget. 2014;5:6512–25.
doi: 10.18632/oncotarget.2270
Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K. et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med. 2002;8:1153–60.
doi: 10.1038/nm761
Rossig L, Jadidi AS, Urbich C, Badorff C, Zeiher AM, Dimmeler S. Akt-dependent phosphorylation of p21(Cip1) regulates PCNA binding and proliferation of endothelial cells. Mol Cell Biol. 2001;21:5644–57.
doi: 10.1128/MCB.21.16.5644-5657.2001
Das S, Ongusaha PP, Yang YS, Park JM, Aaronson SA, Lee SW. Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappa B pathway activation. Cancer Res. 2006;66:8123–30.
doi: 10.1158/0008-5472.CAN-06-1215
Villalba M, Redin E, Exposito F, Pajares MJ, Sainz C, Hervas D. et al. Identification of a novel synthetic lethal vulnerability in non-small cell lung cancer by co-targeting TMPRSS4 and DDR1. Sci Rep. 2019;9:15400.
doi: 10.1038/s41598-019-51066-3
Ambrogio C, Gomez-Lopez G, Falcone M, Vidal A, Nadal E, Crosetto N. et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat Med. 2016;22:270–7.
doi: 10.1038/nm.4041
Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl J Med. 2016;375:1738–48.
doi: 10.1056/NEJMoa1609709
Cristofanilli M, Turner NC, Bondarenko I. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17:E270.
Cristofanilli M, DeMichele A, Giorgetti C, Turner NC, Slamon DJ, Im SA. et al. Predictors of prolonged benefit from palbociclib plus fulvestrant in women with endocrine-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in PALOMA-3. Eur J Cancer. 2018;104:21–31.
doi: 10.1016/j.ejca.2018.08.011
O’Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K. et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8:1390–403.
doi: 10.1158/2159-8290.CD-18-0264
Gordus A, Krall JA, Beyer EM, Kaushansky A, Wolf-Yadlin A, Sevecka M. et al. Linear combinations of docking affinities explain quantitative differences in RTK signaling. Mol Syst Biol. 2009;5:235.
doi: 10.1038/msb.2008.72
Vehlow A, Klapproth E, Jin S, Hannen R, Hauswald M, Bartsch JW. et al. Interaction of discoidin domain receptor 1 with a 14-3-3-beclin-1-Akt1 complex modulates glioblastoma therapy sensitivity. Cell Rep. 2019;26:3672–83.
doi: 10.1016/j.celrep.2019.02.096
Hinds PW, Weinberg RA. Tumor-suppressor genes. Curr Opin Genet Dev. 1994;4:135–41.
doi: 10.1016/0959-437X(94)90102-3
Brennan P, Babbage JW, Burgering BMT, Groner B, Reif K, Cantrell DA. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity. 1997;7:679–89.
doi: 10.1016/S1074-7613(00)80388-X
Dogruluk T, Tsang YH, Espitia M, Chen F, Chen T, Chong Z. et al. Identification of variant-specific functions of PIK3CA by rapid phenotyping of rare mutations. Cancer Res. 2015;75:5341–54.
doi: 10.1158/0008-5472.CAN-15-1654
Hu J, He X, Baggerly KA, Coombes KR, Hennessy BT, Mills GB. Non-parametric quantification of protein lysate arrays. Bioinformatics. 2007;23:1986–94.
doi: 10.1093/bioinformatics/btm283
Ju Z, Liu W, Roebuck PL, Siwak DR, Zhang N, Lu Y. et al. Development of a robust classifier for quality control of reverse-phase protein arrays. Bioinformatics. 2015;31:912–8.
doi: 10.1093/bioinformatics/btu736