Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer

Cancer Research

Volumn 77, Issue 9, 2017, Pages 2488-2499

  Jansen, Valerie M ^a   Bhola, Neil E ^a   Bauer, Joshua A ^a,b   Formisano, Luigi ^a   Lee, Kyung Min ^a   Hutchinson, Katherine E ^a   Witkiewicz, Agnieszka K ^c   Moore, Preston D ^a   Estrada, Mónica Valéria ^a   Sánchez, Violeta ^a   Ericsson, Paula G ^a   Sanders, Melinda E ^a   Pohlmann, Paula R ^d   Pishvaian, Michael J ^d   Riddle, David A ^a   Dugger, Teresa C ^a   Wei, Wenyi ^e   Knudsen, Erik S ^c   Arteaga, Carlos L ^a,b  

^a VANDERBILT INGRAM CANCER CENTER   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF ARIZONA COLLEGE OF MEDICINE   (United States)

^d GEORGETOWN UNIVERSITY   (United States)

^e HARVARD MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALPELISIB; ANTINEOPLASTIC AGENT; CYCLIN A; CYCLIN D1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; CYCLIN E; DINACICLIB; FULVESTRANT; GSK 2334470; PALBOCICLIB; PHOSPHOINOSITIDE DEPENDENT PROTEIN KINASE 1; PROTEIN KINASE B; RIBOCICLIB; UNCLASSIFIED DRUG; AMINOPYRIDINE DERIVATIVE; CDK4 PROTEIN, HUMAN; ESTROGEN RECEPTOR; INDAZOLE DERIVATIVE; PHOSPHATIDYLINOSITOL 3 KINASE; PIPERAZINE DERIVATIVE; PROTEIN SERINE THREONINE KINASE; PURINE DERIVATIVE; PYRIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; PYRUVATE DEHYDROGENASE (ACETYL-TRANSFERRING) KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; CANCER INHIBITION; CANCER RESISTANCE; CELL AGING; CELL CYCLE ARREST; CELL VIABILITY; COMBINATION DRUG THERAPY; CONTROLLED STUDY; DOWN REGULATION; DRUG EFFICACY; DRUG MECHANISM; DRUG POTENTIATION; DRUG SENSITIVITY; ENZYME ACTIVATION; ENZYME INHIBITION; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; FEMALE; HUMAN; HUMAN CELL; IN VIVO STUDY; MCF-7 CELL LINE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; RNA INTERFERENCE; SIGNAL TRANSDUCTION; TUMOR XENOGRAFT; ANIMAL; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; CELL CYCLE CHECKPOINT; CELL PROLIFERATION; DRUG EFFECTS; DRUG RESISTANCE; DRUG SCREENING; GENETICS; PATHOLOGY;

AMINOPYRIDINES; ANIMALS; APOPTOSIS; BREAST NEOPLASMS; CELL CYCLE CHECKPOINTS; CELL PROLIFERATION; CYCLIN-DEPENDENT KINASE 4; CYCLIN-DEPENDENT KINASE 6; DRUG RESISTANCE, NEOPLASM; DRUG SYNERGISM; FEMALE; HUMANS; INDAZOLES; MCF-7 CELLS; MICE; PHOSPHATIDYLINOSITOL 3-KINASES; PIPERAZINES; PROTEIN-SERINE-THREONINE KINASES; PURINES; PYRIDINES; PYRIMIDINES; RECEPTORS, ESTROGEN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 85018607476     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-16-2653     Document Type: Article

References (47)

1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptorpositive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16:25-35.
2. Infante JR, Shapiro G, Witteveen P, Gerecitano JF, Ribrag V, Chugh R, et al. A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas. J Clin Oncol 32:5s, 2014 (suppl; abstr 2528).
3. Shapiro G, Rosen LS, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP, et al. A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. J Clin Oncol 31, 2013 (suppl; abstr 2500).
4. Turner NC, Huang Bartlett C, Cristofanilli M. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 2015; 373:1672-3.
5. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW,Goldman JW, Gandhi L, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740-53.
6. Fry MJ.Phosphoinositide 3-kinase signalling in breast cancer: how big a role might it play? Breast Cancer Res 2001;3:304-12.
7. LinHJ, Hsieh FC, Song H, Lin J. Elevated phosphorylation and activation of PDK-I/AKT pathway in humanbreast cancer. Br JCancer 2005;93:1372-81.
8. Mihaly Z, Kormos M, Lanczky A, Dank M, Budczies J, Szasz MA, et al. A meta-analysis of gene expression-based biomarkers predicting outcome after tamoxifen treatment in breast cancer. Breast Cancer Res Treat 2013;140:219-32.
9. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li QY, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat 2010;123:725-31.
10. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PRJ, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha. Curr Biol 1997; 7:261-9.
11. Mora A, Komander D, van Aalten DMF, Alessi DR. PDK1, the master regulator of AGC kinase signal transduction. Semin Cell Develop Biol 2004;15:161-70.
12. Tan J, Li ZM, Lee PL, Guan PY, Aau MY, Lee ST, et al. PDK1 signaling toward PLK1-MYC activation confers oncogenic transformation, tumor-initiating cell activation, and resistance to mTOR-targeted therapy. Cancer Discov 2013;3:1156-71.
13. Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010;11:9-22.
14. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998;279:710-4.
15. Collins BJ, Deak M, Arthur JSC, Armit LJ, Alessi DR. In vivo role of the PIFbinding docking site of PDK1 defined by knock-in mutation. EMBO J 2003;22:4202-11.
16. Najafov A, Sommer EM, Axten JM, Deyoung MP, Alessi DR. Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem J 2011;433:357-69.
17. Medina JR.Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1. J Med Chem 2013;56:2726-37.
18. Hansen S, Enquist J, Iwig J, Binnerts ME, Jamieson G, Fox JA, et al. Abstract C198: PDK1 inhibitors SNS-229 and SNS-510 cause pathway modulation, apoptosis and tumor regression in hematologic cancer models in addition to solid tumors. Mol Cancer Ther 2015;14:C198.
19. Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M, Gao D, et al. Cellcycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 2014;508:541-5.
20. Miller TW, Hennessy BT, Gonzalez-AnguloAM, Fox EM, Mills GB, Chen H, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 2010;120:2406-13.
21. Xiang B, Muthuswamy SK. Using three-dimensional acinar structures for molecular and cell biological assays. Method Enzymol 2006;406:692-701.
22. Swanton C, Marani M, Pardo O, Warne PH, Kelly G, Sahai E, et al. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell 2007;11:498-512.
23. Bauer JA, Ye F, Marshall CB, Lehmann BD, Pendleton CS, Shyr Y, et al. RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells. Breast Cancer Res 2010;12:R41.
24. Ye F, Bauer JA, Pietenpol JA, Shyr Y. Analysis of high-throughput RNAi screening data in identifying genes mediating sensitivity to chemotherapeutic drugs: statistical approaches and perspectives. BMC Genomics 2012;13:S3.
25. Medina JR, Becker CJ, Blackledge CW, Duquenne C, Feng Y, Grant SW, et al. Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. J Med Chem 2011;54:1871-95.
26. Chou TC.Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006;58:621-81.
27. Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regulat 1984;22:27-55.
28. Edmondson R, Broglie JJ, Adcock AF, Yang LJ. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol 2014;12:207-18.
29. Pickl M, Ries CH. Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab. Oncogene 2009;28:461-8.
30. Pampaloni F, Reynaud EG, Stelzer EHK. The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol 2007;8:839-45.
31. O'Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol 2016;13:417-30.
32. 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.
33. Kitagawa M, Higashi H, Jung HK, SuzukiTakahashi I, Ikeda M, Tamai K, et al. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2. EMBO J 1996;15:7060-9.
34. Mayer IA, Abramson V, Formisano L, Balko JM, Estrada MV, Sanders M, et al. A phase Ib study of alpelisib (BYL719), a PI3Kalpha-specific inhibitor, with letrozole in ER+/HER2-negativemetastatic breast cancer. Clin Cancer Res 2017;23:26-34.
35. Juric D, Rodon J, Gonzalez-Angulo AM, Burris HA, Bendell J, Berlin JD, et al. BYL719, a next generation PI3K alpha specific inhibitor: preliminary safety, PK, and efficacy results from the first-in-human study [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; 2012. Abstract nr CT-01.
36. 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 Res 2016;76:2301-13.
37. Donjerkovic D, Scott DW. Regulation of the G1 phase of the mammalian cell cycle. Cell Res 2000;10:1-16.
38. Bertoli C, Skotheim JM, de Bruin RAM. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol 2013;14:518-28.
39. Parry D, Guzi T, Shanahan F, Davis N, Prabhavalkar D, Wiswell D, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther 2010;9:2344-53.
40. 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.
41. Bauer JA, Ye F, Marshall CB, Lehmann BD, Pendleton CS, Shyr Y, et al. RNA interference (RNAi) screening approach identifies agents that enhance paclitaxel activity in breast cancer cells. Breast Cancer Res 2010;12:R41.
42. Kwong LN, Costello JC, Liu HY, Jiang S, Helms TL, Langsdorf AE, et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat Med 2012;18:1503-U96.
43. Ziemke EK, Dosch JS, Maust JD, Shettigar A, Sen A, Welling TH, et al. Sensitivity of KRAS-mutant colorectal cancers to combination therapy that cotargets MEK and CDK4/6. Clin Cancer Res 2016;22:405-14.
44. Yadav V, Burke TF, Huber L, Van Horn RD, Zhang YY, Buchanan SG, et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and Cyclin D1 upregulation. Mol Cancer Ther 2014;13:2253-63.
45. Castel P, Ellis H, Bago R, Toska E, Razavi P, Carmona FJ, et al. PDK1-SGK1 signaling sustains AKT-independent mTORC1 activation and confers resistance to PI3Kalpha inhibition. Cancer Cell 2016;30:229-42.
46. Maira SM. PI3K inhibitors for cancer treatment: five years of preclinical and clinical research after BEZ235. Mol Cancer Ther 2011;10:2016.
47. Mateo J, De Bono JS, Ramanathan RK, Lustberg MB, Zivi A, Basset D, et al. A first-in-human phase I trial of AR-12, a PDK-1 inhibitor, in patients with advanced solid tumors. J Clin Oncol 31, 2013 (suppl. abstr 2608).