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Review

Potential Prospect of CDK4/6 Inhibitors in Triple-Negative Breast Cancer

ORCID Icon, , ORCID Icon &
Pages 5223-5237 | Published online: 01 Jul 2021

References

  • Sung H , Ferlay J , Siegel RL , et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin . 2021;71(3):209–249. doi:10.3322/caac.21660 33538338
  • Parise CA , Caggiano V . Breast cancer survival defined by the ER/PR/HER2 subtypes and a surrogate classification according to tumor grade and immunohistochemical biomarkers. J Cancer Epidemiol . 2014;2014:1–11. doi:10.1155/2014/469251
  • Bianchini G , Balko JM , Mayer IA , Sanders ME , Gianni L . Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol . 2016;13:674–690. doi:10.1038/nrclinonc.2016.66 27184417
  • Lehmann BD , Bauer JA , Chen X , et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest . 2011;121:2750–2767. doi:10.1172/JCI45014 21633166
  • Jiang YZ , Ma D , Suo C , et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell . 2019;35:428–440. doi:10.1016/j.ccell.2019.02.001 30853353
  • Li Y , Rogoff HA , Keates S , et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA . 2015;112:1839–1844. doi:10.1073/pnas.1424171112 25605917
  • Robson M , Im SA , Senkus E , et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med . 2017;377:523–533. doi:10.1056/NEJMoa1706450 28578601
  • Schmid P , Adams S , Rugo HS , et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med . 2018;379:2108–2121. doi:10.1056/NEJMoa1809615 30345906
  • Heimes AS , Schmidt M . Atezolizumab for the treatment of triple-negative breast cancer. Expert Opin Investig Drugs . 2019;28:1–5. doi:10.1080/13543784.2019.1552255
  • Romero D . Benefit in patients with PD-L1-positive TNBC. Nat Rev Clin Oncol . 2019;16:6.
  • Hanahan D , Weinberg RA . Hallmarks of cancer: the next generation. Cell . 2011;144:646–674. doi:10.1016/j.cell.2011.02.013 21376230
  • Arnold A , Papanikolaou A . Cyclin D1 in breast cancer pathogenesis. J Clin Oncol . 2005;23:4215–4224. doi:10.1200/JCO.2005.05.064 15961768
  • Yu Q , Geng Y , Sicinski P . Specific protection against breast cancers by cyclin D1 ablation. Nature . 2001;411:1017–1021. doi:10.1038/35082500 11429595
  • Cretella D , Ravelli A , Fumarola C , et al. The anti-tumor efficacy of CDK4/6 inhibition is enhanced by the combination with PI3K/AKT/mTOR inhibitors through impairment of glucose metabolism in TNBC cells. J Exp Clin Cancer Res . 2018;37. doi:10.1186/s13046-018-0741-3
  • Clark AS , Karasic TB , DeMichele A , et al. Palbociclib (PD0332991) — a selective and potent cyclin-dependent kinase inhibitor A review of pharmacodynamics and clinical development. JAMA Oncol . 2016;2:253–260. doi:10.1001/jamaoncol.2015.4701 26633733
  • Finn RS , Dering J , Conklin D , 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:R77. doi:10.1186/bcr2419 19874578
  • Ingham M , Schwartz GK . Cell-cycle therapeutics come of age. J Clin Oncol . 2017;35:2949–2959. doi:10.1200/JCO.2016.69.0032 28580868
  • Deshpande A , Sicinski P , Hinds PW . Cyclins and cdks in development and cancer: a perspective. Oncogene . 2005;24:2909–2915. doi:10.1038/sj.onc.1208618 15838524
  • Hochegger H , Takeda S , Hunt T . Cyclin-dependent kinases and cell-cycle transitions: does one fit all. Nat Rev Mol Cell Biol . 2008;9:910–916. doi:10.1038/nrm2510 18813291
  • Schachter MM , Merrick KA , Larochelle S , et al. A Cdk7-Cdk4 T-loop phosphorylation cascade promotes G1 progression. Mol Cell . 2013;50:250–260. doi:10.1016/j.molcel.2013.04.003 23622515
  • Pandey K , An HJ , Kim SK , et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer . 2019;145:1179–1188. doi:10.1002/ijc.32020 30478914
  • Trimarchi JM , Lees JA . Sibling rivalry in the E2F family. Nat Rev Mol Cell Biol . 2002;3:11–20. doi:10.1038/nrm714 11823794
  • Massagué J . G1 cell-cycle control and cancer. Nature . 2004;432:298–306. doi:10.1038/nature03094 15549091
  • Pardee AB . G1 events and regulation of cell proliferation. Science . 1989;246:603–608. doi:10.1126/science.2683075 2683075
  • Matsushime H , Roussel MF , Ashmun RA , Sherr CJ . Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell . 1991;65:701–713. doi:10.1016/0092-8674(91)90101-4 1827757
  • Meyerson M , Harlow E . Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol . 1994;14:2077–2086. doi:10.1128/mcb.14.3.2077-2086.1994 8114739
  • Canepa ET , Scassa ME , Ceruti JM , et al. INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. Iubmb Life . 2007;59:419–426. doi:10.1080/15216540701488358 17654117
  • Spencer SL , Cappell SD , Tsai F , Overton KW , Wang CL , Meyer T . The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell . 2013;155:369–383. doi:10.1016/j.cell.2013.08.062 24075009
  • Gong X , Litchfield LM , Webster Y , et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell . 2017;32:761–776. doi:10.1016/j.ccell.2017.11.006 29232554
  • Sherr CJ , Roberts JM . CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev . 1999;13:1501–1512. doi:10.1101/gad.13.12.1501 10385618
  • Harper JW , Adami GR , Wei N , Keyomarsi K , Elledge SJ . The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell . 1993;75:805–816. doi:10.1016/0092-8674(93)90499-G 8242751
  • Blain SW , Montalvo E , Massague J . Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4. J Biol Chem . 1997;272:25863–25872. doi:10.1074/jbc.272.41.25863 9325318
  • Senderowicz AM . Flavopiridol: the first cyclin-dependent kinase inhibitor in human clinical trials. Invest New Drugs . 1999;17:313–320. doi:10.1023/A:1006353008903 10665481
  • Shapiro GI . Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol . 2006;24:1770–1783. doi:10.1200/JCO.2005.03.7689 16603719
  • Konecny GE . Cyclin-dependent kinase pathways as targets for women’s cancer treatment. Curr Opin Obstet Gynecol . 2016;28:42–48. doi:10.1097/GCO.0000000000000243 26642065
  • Kouroukis CT , Belch A , Crump M , et al. Flavopiridol in untreated or relapsed mantle-cell lymphoma: results of a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol . 2003;21:1740–1745. doi:10.1200/JCO.2003.09.057 12735303
  • Jessen BA , Lee L , Koudriakova T , et al. Peripheral white blood cell toxicity induced by broad spectrum cyclin-dependent kinase inhibitors. J Appl Toxicol . 2007;27:133–142. doi:10.1002/jat.1177 17211896
  • Parry D , Guzi T , Shanahan F , et al. Dinaciclib (SCH 727965), a novel and potent cyclin dependent kinase inhibitor. Mol Cancer Ther . 2010;9:2344–2353. doi:10.1158/1535-7163.MCT-10-0324 20663931
  • Fry DW , Harvey PJ , Keller PR , et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther . 2004;3:1427–1438.15542782
  • Finn RS , Crown JP , Lang I , et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised Phase 2 study. Lancet Oncol . 2015;16:25–35. doi:10.1016/S1470-2045(14)71159-3 25524798
  • Hortobagyi GN , Stemmer SM , Burris HA , et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med . 2018;379:2582.30586508
  • Dickler MN , Tolaney SM , Rugo HS , et al. MONARCH 1, A Phase II Study of abemaciclib, a CDK4 and CDK6 Inhibitor, as a single agent, in patients with refractory HR(+)/HER2(-) metastatic breast cancer. Clin Cancer Res . 2017;23:5218–5224. doi:10.1158/1078-0432.CCR-17-0754 28533223
  • Sledge GJ , Toi M , Neven P , et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol . 2017;35:2875–2884. doi:10.1200/JCO.2017.73.7585 28580882
  • Finn RS , Martin M , Rugo HS , et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med . 2016;375:1925–1936. doi:10.1056/NEJMoa1607303 27959613
  • Cristofanilli M , Turner NC , Bondarenko I , et al. 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;17:425–439. doi:10.1016/S1470-2045(15)00613-0 26947331
  • Carey LA , Dees EC , Sawyer L , et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res . 2007;13:2329–2334. doi:10.1158/1078-0432.CCR-06-1109 17438091
  • Dent R , Trudeau M , Pritchard KI , et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res . 2007;13:4429–4434. doi:10.1158/1078-0432.CCR-06-3045 17671126
  • Carey L , Winer E , Viale G , Cameron D , Gianni L . Triple-negative breast cancer: disease entity or title of convenience? Nat Rev Clin Oncol . 2010;7:683–692. doi:10.1038/nrclinonc.2010.154 20877296
  • Yin WJ , Lu JS , Di GH , et al. Clinicopathological features of the triple-negative tumors in Chinese breast cancer patients. Breast Cancer Res Treat . 2009;115:325–333. doi:10.1007/s10549-008-0096-0 18563552
  • Dignam JJ , Dukic V , Anderson SJ , Mamounas EP , Wickerham DL , Wolmark N . Hazard of recurrence and adjuvant treatment effects over time in lymph node-negative breast cancer. Breast Cancer Res Treat . 2009;116:595–602. doi:10.1007/s10549-008-0200-5 18830816
  • Ciriello G , Gatza ML , Beck AH , et al. Comprehensive molecular portraits of human breast tumours. Nature . 2012;490:61–70.23000897
  • An O , Dall’Olio GM , Mourikis TP , Ciccarelli FD . NCG 5.0: updates of a manually curated repository of cancer genes and associated properties from cancer mutational screenings. Nucleic Acids Res . 2016;44:D992–9. doi:10.1093/nar/gkv1123 26516186
  • Asghar US , Barr AR , Cutts R , et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin Cancer Res . 2017;23:5561–5572. doi:10.1158/1078-0432.CCR-17-0369 28606920
  • Dean JL , McClendon AK , Hickey TE , et al. Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle . 2012;11:2756–2761. doi:10.4161/cc.21195 22767154
  • Condorelli R , Spring L , O’Shaughnessy J , et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol . 2018;29:640–645. doi:10.1093/annonc/mdx784 29236940
  • O’Leary B , Finn RS , Turner NC . Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol . 2016;13:417–430. doi:10.1038/nrclinonc.2016.26 27030077
  • Wiedemeyer WR , Dunn IF , Quayle SN , et al. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci U S A . 2010;107:11501–11506. doi:10.1073/pnas.1001613107 20534551
  • Witkiewicz AK , Knudsen KE , Dicker AP , Knudsen ES . The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle . 2011;10:2497–2503. doi:10.4161/cc.10.15.16776 21775818
  • Tort F , Bartkova J , Sehested M , Orntoft T , Lukas J , Bartek J . Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis. Cancer Res . 2006;66:10258–10263. doi:10.1158/0008-5472.CAN-06-2178 17079443
  • Vijayaraghavan S , Karakas C , Doostan I , et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat Commun . 2017;8:15916. doi:10.1038/ncomms15916 28653662
  • Rubin SM . Deciphering the retinoblastoma protein phosphorylation code. Trends Biochem Sci . 2013;38:12–19. doi:10.1016/j.tibs.2012.10.007 23218751
  • Weintraub SJ , Chow KN , Luo RX , Zhang SH , He S , Dean DC . Mechanism of active transcriptional repression by the retinoblastoma protein. Nature . 1995;375:812–815. doi:10.1038/375812a0 7596417
  • Harbour JW , Luo RX , Dei Santi A , Postigo AA , Dean DC . Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell . 1999;98:859–869. doi:10.1016/S0092-8674(00)81519-6 10499802
  • Hiebert SW , Chellappan SP , Horowitz JM , Nevins JR . The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes Dev . 1992;6:177–185. doi:10.1101/gad.6.2.177 1531329
  • Brasca MG , Amboldi N , Ballinari D , et al. Identification of N,1,4,4-tetramethyl-8-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA-848125), a potent, orally available cyclin dependent kinase inhibitor. J Med Chem . 2009;52:5152–5163. doi:10.1021/jm9006559 19603809
  • Glick D , Barth S , Macleod KF . Autophagy: cellular and molecular mechanisms. J Pathol . 2010;221:3–12. doi:10.1002/path.2697 20225336
  • Wang R , Zhang Q , Peng X , et al. Stellettin B induces G1 arrest, apoptosis and autophagy in human non-small cell lung cancer A549 cells via blocking PI3K/Akt/mTOR pathway. Sci Rep . 2016;6:27071. doi:10.1038/srep27071 27243769
  • Chittaranjan S , Bortnik S , Dragowska WH , et al. Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and -resistant triple-negative breast cancer. Clin Cancer Res . 2014;20:3159–3173. doi:10.1158/1078-0432.CCR-13-2060 24721646
  • Collins LC , Cole KS , Marotti JD , et al. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Mod Pathol . 2011;24(7):924–931. doi:10.1038/modpathol.2011.54 21552212
  • Gasparini P , Fassan M , Cascione L , et al. Androgen receptor status is a prognostic marker in non-basal triple negative breast cancers and determines novel therapeutic options. PLoS One . 2014;9(2):e88525. doi:10.1371/journal.pone.0088525 24505496
  • Safarpour D , Tavassoli AT . A targetable androgen receptor-positive breast cancer subtype hidden among the triple-negative cancers. Arch Pathol Lab Med . 2015;139(5):612–617. doi:10.5858/arpa.2014-0122-RA 25310144
  • Mrklić L , Pogorelić Z , Capkun V , Tomić S . Expression of androgen receptors in triple negative breast carcinomas. Acta Histochem . 2013;115(4):344–348. doi:10.1016/j.acthis.2012.09.006 23031358
  • McNamara KM , Yoda T , Miki Y , et al. Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation. Cancer Sci . 2013;104(5):639–646. doi:10.1111/cas.12121 23373898
  • Scher HI , Fizazi K , Saad F , et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med . 2012;367:1187–1197. doi:10.1056/NEJMoa1207506 22894553
  • Beer TM , Armstrong AJ , Rathkopf DE , et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med . 2014;371:424–433. doi:10.1056/NEJMoa1405095 24881730
  • Doane AS , Danso M , Lal P , et al. An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen. Oncogene . 2006;25:3994–4008. doi:10.1038/sj.onc.1209415 16491124
  • Liu CY , Lau KY , Hsu CC , et al. Combination of palbociclib with enzalutamide shows in vitro activity in RB proficient and androgen receptor positive triple negative breast cancer cells. PLoS One . 2017;12:e189007. doi:10.1371/journal.pone.0189007
  • Ji W , Shi Y , Wang X , et al. Combined androgen receptor blockade overcomes the resistance of breast cancer cells to palbociclib. Int J Biol Sci . 2019;15:522–532. doi:10.7150/ijbs.30572 30745839
  • Pawson T , Nash P . Assembly of cell regulatory systems through protein interaction domains. Science . 2003;300:445–452. doi:10.1126/science.1083653 12702867
  • Lannutti BJ , Meadows SA , Herman SE , et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood . 2011;117:591–594. doi:10.1182/blood-2010-03-275305 20959606
  • Engelman JA , Luo J , Cantley LC . The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet . 2006;7:606–619. doi:10.1038/nrg1879 16847462
  • Salmena L , Carracedo A , Pandolfi PP . Tenets of PTEN tumor suppression. Cell . 2008;133:403–414. doi:10.1016/j.cell.2008.04.013 18455982
  • Hill MM , Hemmings BA . Inhibition of protein kinase B/Akt. implications for cancer therapy. Pharmacol Ther . 2002;93:243–251. doi:10.1016/S0163-7258(02)00193-6 12191616
  • Zoncu R , Efeyan A , Sabatini DM . mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol . 2011;12:21–35. doi:10.1038/nrm3025 21157483
  • Nojima H , Tokunaga C , Eguchi S , et al. The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif. J Biol Chem . 2003;278:15461–15464. doi:10.1074/jbc.C200665200 12604610
  • Diehl JA , Cheng M , Roussel MF , Sherr CJ . Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev . 1998;12:3499–3511. doi:10.1101/gad.12.22.3499 9832503
  • Albers MW , Williams RT , Brown EJ , Tanaka A , Hall FL , Schreiber SL . FKBP-rapamycin inhibits a cyclin-dependent kinase activity and a cyclin D1-Cdk association in early G1 of an osteosarcoma cell line. J Biol Chem . 1993;268:22825–22829. doi:10.1016/S0021-9258(18)41602-X 8226793
  • Zacharek SJ , Xiong Y , Shumway SD . Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer Res . 2005;65:11354–11360. doi:10.1158/0008-5472.CAN-05-2236 16357142
  • Vora SR , Juric D , Kim N , et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell . 2014;26:136–149. doi:10.1016/j.ccr.2014.05.020 25002028
  • Ku BM , Yi SY , Koh J , et al. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget . 2016;7:14803–14813. doi:10.18632/oncotarget.7543 26909611
  • Michaloglou C , Crafter C , Siersbaek R , et al. Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long-term growth inhibition in estrogen receptor-positive breast cancer. Mol Cancer Ther . 2018;17:908–920. doi:10.1158/1535-7163.MCT-17-0537 29483206
  • Yu KD , Zhu R , Zhan M , et al. Identification of prognosis-relevant subgroups in patients with chemoresistant triple-negative breast cancer. Clin Cancer Res . 2013;19:2723–2733. doi:10.1158/1078-0432.CCR-12-2986 23549873
  • Courtney KD , Corcoran RB , Engelman JA . The PI3K pathway as drug target in human cancer. J Clin Oncol . 2010;28:1075–1083. doi:10.1200/JCO.2009.25.3641 20085938
  • Fedele CG , Ooms LM , Ho M , et al. Inositol polyphosphate 4-phosphatase II regulates PI3K/Akt signaling and is lost in human basal-like breast cancers. Proc Natl Acad Sci U S A . 2010;107:22231–22236. doi:10.1073/pnas.1015245107 21127264
  • Zhang J , Xu K , Liu P , et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell . 2016;62:929–942. doi:10.1016/j.molcel.2016.04.023 27237051
  • Teo ZL , Versaci S , Dushyanthen S , et al. Combined CDK4/6 and PI3Kalpha inhibition is synergistic and immunogenic in triple-negative breast cancer. Cancer Res . 2017;77:6340–6352. doi:10.1158/0008-5472.CAN-17-2210 28947417
  • Yamamoto T , Kanaya N , Somlo G , Chen S . Synergistic anti-cancer activity of CDK4/6 inhibitor palbociclib and dual mTOR kinase inhibitor MLN0128 in pRb-expressing ER-negative breast cancer. Breast Cancer Res Treat . 2019;174:615–625. doi:10.1007/s10549-018-05104-9 30607633
  • Revathidevi S , Munirajan AK . Akt in cancer: mediator and more. Semin Cancer Biol . 2019;59:80–91. doi:10.1016/j.semcancer.2019.06.002 31173856
  • Costa C , Wang Y , Ly A , et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer Discov . 2020;10(1):72–85. doi:10.1158/2159-8290.CD-18-0830 31594766
  • Lopez-Knowles E , O’Toole SA , McNeil CM , et al. PI3K pathway activation in breast cancer is associated with the basal-like phenotype and cancer-specific mortality. Int J Cancer . 2010;126:1121–1131. doi:10.1002/ijc.24831 19685490
  • Saal LH , Holm K , Maurer M , et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res . 2005;65:2554–2559. doi:10.1158/0008-5472-CAN-04-3913 15805248
  • Perez-Tenorio G , Alkhori L , Olsson B , et al. PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res . 2007;13:3577–3584. doi:10.1158/1078-0432.CCR-06-1609 17575221
  • Betts G , Twohig J , Van den Broek M , Sierro S , Godkin A , Gallimore A . The impact of regulatory T cells on carcinogen-induced sarcogenesis. Br J Cancer . 2007;96:1849–1854. doi:10.1038/sj.bjc.6603824 17565340
  • Kimura H , Nakamura T , Ogawa T , Tanaka S , Shiota K . Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Nucleic Acids Res . 2003;31:3101–3113. doi:10.1093/nar/gkg406 12799438
  • Goel S , DeCristo MJ , Watt AC , et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature . 2017;548:471–475. doi:10.1038/nature23465 28813415
  • Bauer CA , Kim EY , Marangoni F , Carrizosa E , Claudio NM , Mempel TR . Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest . 2014;124:2425–2440. doi:10.1172/JCI66375 24812664
  • Zhang J , Bu X , Wang H , et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature . 2018;553:91–95. doi:10.1038/nature25015 29160310
  • Chabottaux V , Sounni NE , Pennington CJ , et al. Membrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases. Cancer Res . 2006;66:5165–5172. doi:10.1158/0008-5472.CAN-05-3012 16707440
  • Nielsen TO , Hsu FD , Jensen K , et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res . 2004;10:5367–5374. doi:10.1158/1078-0432.CCR-04-0220 15328174
  • Yip C , Foidart P , Somja J , et al. MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib. Br J Cancer . 2017;116:742–751. doi:10.1038/bjc.2017.23 28196064
  • Paye A , Truong A , Yip C , et al. EGFR activation and signaling in cancer cells are enhanced by the membrane-bound metalloprotease MT4-MMP. Cancer Res . 2014;74:6758–6770. doi:10.1158/0008-5472.CAN-13-2994 25320013
  • Host L , Paye A , Detry B , et al. The proteolytic activity of MT4-MMP is required for its pro-angiogenic and pro-metastatic promoting effects. Int J Cancer . 2012;131:1537–1548. doi:10.1002/ijc.27436 22262494
  • Foidart P , Yip C , Radermacher J , et al. Expression of MT4-MMP, EGFR, and RB in triple-negative breast cancer strongly sensitizes tumors to erlotinib and palbociclib combination therapy. Clin Cancer Res . 2019;25:1838–1850. doi:10.1158/1078-0432.CCR-18-1880 30504427
  • Schickling O , Stegh AH , Byrd J , Peter ME . Nuclear localization of DEDD leads to caspase-6 activation through its death effector domain and inhibition of RNA polymerase I dependent transcription. Cell Death Differ . 2001;8:1157–1168. doi:10.1038/sj.cdd.4400928 11753564
  • Ni Y , Schmidt KR , Werner BA , et al. Death effector domain-containing protein induces vulnerability to cell cycle inhibition in triple-negative breast cancer. Nat Commun . 2019;10:2869. doi:10.1038/s41467-019-10743-7 31253776
  • Beslija S , Bonneterre J , Burstein H , et al. Third Consensus on medical treatment of metastatic breast cancer. Ann Oncol . 2009;20:1771–1785. doi:10.1093/annonc/mdp261 19608616
  • Malhotra MK , Emens LA . The evolving management of metastatic triple negative breast cancer. Semin Oncol . 2020;47(4):229–237. doi:10.1053/j.seminoncol.2020.05.005 32563561
  • Dean JL , McClendon AK , Knudsen ES . Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem . 2012;287:29075–29087. doi:10.1074/jbc.M112.365494 22733811
  • He S , Roberts PJ , Sorrentino JA , et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med . 2017;9(387):eaal3986. doi:10.1126/scitranslmed.aal3986 28446688
  • Roskoski R Jr . Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol Res . 2019;139:471–488. doi:10.1016/j.phrs.2018.11.035 30508677
  • Tan AR , Wright GS , Thummala AR , et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol . 2019;20(11):1587–1601. doi:10.1016/S1470-2045(19)30616-3 31575503
  • Cretella D , Fumarola C , Bonelli M , et al. Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells. Sci Rep . 2019;9:13014. doi:10.1038/s41598-019-49484-4 31506466
  • Sonoda E , Sasaki MS , Buerstedde JM , et al. Rad51-deficient vertebrate cells accumulate chromosomal breaks prior to cell death. EMBO J . 1998;17:598–608. doi:10.1093/emboj/17.2.598 9430650
  • Schwartz GK , LoRusso PM , Dickson MA , et al. Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1). Br J Cancer . 2011;104:1862–1868. doi:10.1038/bjc.2011.177 21610706
  • Clark AS , McAndrew NP , Troxel A , et al. Combination paclitaxel and palbociclib: results of a Phase I Trial in advanced breast cancer. Clin Cancer Res . 2019;25(7):2072–2079. doi:10.1158/1078-0432.CCR-18-0790 30635336
  • Ayca G , Leigh AB , Tina A , et al. Phase II trial of bicalutamide in combination with palbociclib for the treatment of androgen receptor (+) metastatic breast cancer. J Clin Oncol . 2020;15:1017.
  • Sharifi M , Wisinski KB , Burkard ME , et al. Phase I trial of bicalutamide and ribociclib in androgen receptor-positive triple negative breast cancer. Available from: https://www.abstracts2view.com/sabcs18/view.php?nu=SABCS18L_297. Accessed 12 5, 2018.
  • Jiang YZ , Liu Y , Xiao Y , et al. Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial. Cell Res . 2021;31(2):178–186. doi:10.1038/s41422-020-0375-9 32719455