Abstract
Abnormal activation of the cyclin-dependent kinases (CDKs), which result in aberrant cell proliferation, is one of the inherent characteristics of tumor. Thus targeting the activity of CDKs represents a promising tumor therapeutic strategy. Currently, the specific inhibitors that target CDK4 and CDK6 have been approved for the treatment of estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER+ HER2−) breast cancer in combination with endocrine therapy; other combination strategies are being tested in a number of clinical trials. However, the acquired resistance to CDK4/6 inhibitors has emerged. As the cell cycle is orchestrated by a series of biological events, the alterations of other molecular events that regulate the cell cycle progression may be involved in intrinsic resistance to CDK4/6 inhibitors. In this review we mainly discuss the mechanisms underlying intrinsic resistance and acquired resistance to CDK4/6 inhibitors as well as combination strategies with other signal pathway inhibitors being tested in clinical and pre-clinical studies, to extend the use of CDK4/6 inhibitors in tumor treatment.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432:316–23.
Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30.
Hannon GJ, Beach D. p15INK4b is a potential effector of TGF-beta-induced cell cycle arrest. Nature. 1994;371:257–61.
Hirai H, Roussel MF, Kato JY, Ashmun RA, Sherr CJ. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases CDK4 and CDK6. Mol Cell Biol. 2015;15:2672–81.
Chan FK, Zhang J, Cheng L, Shapiro DN, Winoto A. Identification of human and mouse p19, a novel CDK4 and CDK6 inhibitor with homology to p16ink4. Mol Cell Biol. 2015;15:2682–8.
Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.
Hoffmann J, Bohlmann R, Heinrich N, Hofmeister H, Kroll J, Künzer H, et al. Characterization of new estrogen receptor destabilizing compounds: effects on estrogen-sensitive and tamoxifen-resistant breast cancer. J Natl Cancer Inst. 2004;96:210–8.
Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18:1–11.
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;11:1–13.
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 receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16:25–35.
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.
Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638–46.
Rinnerthaler G, Gampenrieder SP, Greil R. ASCO 2018 highlights: metastatic breast cancer. Memo - Mag Eur Med Oncol. 2018;11:276–9.
Johnson J, Thijssen B, McDermott U, Garnett M, Wessels LF, Bernards R. Targeting the RB-E2F pathway in breast cancer. Oncogene. 2016;35:4829–35.
Konecny GE, Winterhoff B, Kolarova T, Qi J, Manivong K, Dering J, et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res. 2011;17:1591–602.
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;10:2497–503.
Aagaard L, Lukas J, Bartkova J, Kjerulff AA, Strauss M, Bartek J. Aberrations of p16Ink4 and retinoblastoma tumor-suppressor genes occur in distinct sub-sets of human cancer cell lines. Int J Cancer. 1995;61:115–20.
Rubio C, Martínez-Fernández M, Segovia C, Lodewijk I, Suarez-Cabrera C, Segrelles C, et al. CDK4/6 inhibitor as a novel therapeutic approach for advanced bladder cancer independently of RB1 status. Clin Cancer Res. 2019;25:390–402.
Condorelli R, Spring L, O’Shaughnessy J, Lacroix L, Bailleux C, Scott V, et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol. 2018;29:640–5.
Kent LN, Leone G. The broken cycle: E2F dysfunction in cancer. Nat Rev Cancer. 2019;19:326–38.
Guerrero-Zotano AL, Stricker TP, Formisano L, Hutchinson KE, Stover DG, Lee KM, et al. ER+ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors. Clin Cancer Res. 2018;24:2517–29.
Chen SH, Gong X, Zhang Y, Van Horn RD, Yin T, Huber L, et al. RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1. Oncogene. 2018;37:821–32.
Schmidt EE, Ichimura K, Reifenberger G, Collins VP. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 1994;54:6321–4.
Chawla R, Procknow JA, Tantravahi RV, Khurana JS, Litvin J, Reddy EP. Cooperativity of Cdk4R24C and Ras in melanoma development. Cell Cycle. 2010;9:3305–14.
Olanich ME, Sun W, Hewitt SM, Abdullaev Z, Pack SD, Barr FG. CDK4 amplification reduces sensitivity to CDK4/6 inhibition in fusion-positive rhabdomyosarcoma. Clin Cancer Res. 2015;21:4947–59.
Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31:2024–8.
Geoerger B, Bourdeaut F, DuBois SG, Fischer M, Geller JI, Gottardo NG, et al. A phase I study of the CDK4/6 inhibitor ribociclib (LEE011) in pediatric patients with malignant rhabdoid tumors, neuroblastoma, and other solid tumors. Clin Cancer Res. 2017;23:2433–41.
Raspé E, Coulonval K, Pita JM, Paternot S, Rothé F, Twyffels L, et al. CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib. EMBO Mol Med. 2017;9:1052–66.
Malumbres M, Sotillo R, Santamaría D, Galán J, Cerezo A, Ortega S, et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell. 2004;118:493–504.
Spencer SL, Cappell SD, Tsai FC, Overton KW, Wang CL, Meyer T. The proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell. 2013;155:369–83.
Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D, et al. Single-cell dynamics determines response to CDK4/6 inhibition in triple negative breast cancer. Clin Cancer Res. 2017;23:5561–72.
Gong X, Litchfield LM, Webster Y, Chio LC, Wong SS, Stewart TR, et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor Abemaciclib. Cancer Cell. 2017;32:761–76.
Xue Y, Meehan B, Macdonald E, Venneti S, Wang XQD, Witkowski L, et al. CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary. Nat Commun. 2019;10:558.
Xue Y, Meehan B, Fu Z, Wang XQD, Fiset PO, Rieker R, et al. SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat Commun. 2019;10:557.
Santala S, Talvensaari-Mattila A, Soini Y, Santala M. Cyclin E expression correlates with cancer-specific survival in endometrial endometrioid adenocarcinoma. Anticancer Res. 2015;35:3393–7.
Zhao ZM, Yost SE, Hutchinson KE, Li SM, Yuan YC, Noorbakhsh J, et al. CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer. BMC Cancer. 2019;19:1–11.
Min A, Kim JE, Kim YJ, Lim JM, Kim S, Kim JW, et al. Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells. Cancer Lett. 2018;430:123–32.
Chandarlapaty S, Razavi P. Cyclin E mRNA: assessing cyclin-dependent kinase (CDK) activation state to elucidate breast cancer resistance to CDK4/6 inhibitors. J Clin Oncol. 2019;37:1148–50.
Rocco JW, Sidransky D. p16(MTS-1/CDKN2/INK4a) in cancer progression. Exp Cell Res. 2001;264:42–55.
Young RJ, Waldeck K, Martin C, Foo JH, Cameron DP, Kirby L, et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res. 2014;27:590–600.
Heilmann AM, Perera RM, Ecker V, Nicolay BN, Bardeesy N, Benes CH, et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 2014;74:3947–58.
Cen L, Carlson BL, Schroeder MA, Ostrem JL, Kitange GJ, Mladek AC, et al. p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro Oncol. 2012;14:870–81.
Engeland K. Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ. 2018;25:114–32.
Cox LS. Multiple pathways control cell growth and transformation: overlapping and independent activities of p53 and p21cip/WAF1/Sdi1. J Pathol. 1997;183:134–40.
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.
Fernández-Aroca DM, Roche O, Sabater S, Pascual-Serra R, Ortega-Muelas M, Sánchez Pérez I, et al. P53 pathway is a major determinant in the radiosensitizing effect of Palbociclib: implication in cancer therapy. Cancer Lett. 2019;451:23–33.
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, et al. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065–70.
Lin SL, Chang DC, Ying SY, Leu D, Wu DT. MicroRNA miR-302 inhibits the tumorigenecity of human pluripotent stem cells by coordinate suppression of the CDK2 and CDK4/6 cell cycle pathways. Cancer Res. 2010;70:9473–82.
Qiu S, Huang D, Yin D, Li F, Li X, Kung HF, et al. Suppression of tumorigenicity by MicroRNA-138 through inhibition of EZH2-CDK4/6-pRb-E2F1 signal loop in glioblastoma multiforme. Biochim Biophys Acta - Mol Basis Dis. 2013;1832:1697–707.
Liu G, Sun Y, Ji P, Li X, Cogdell D, Yang D, et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol. 2014;233:308–18.
Lulla AR, Slifker MJ, Zhou Y, Lev A, Einarson MB, Dicker DT, et al. miR-6883 family miRNAs target CDK4/6 to induce G1 phase cell-cycle arrest in colon cancer cells. Cancer Res. 2017;77:6902–13.
Cornell L, Wander SA, Visal T, Wagle N, Shapiro GI. MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep. 2019;26:2667–80.
Torii S, Yamamoto T, Tsuchiya Y, Nishida E. ERK MAP kinase in G1 cell cycle progression and cancer. Cancer Sci. 2006;97:697–702.
Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10:1–14.
Haines E, Chen T, Kommajosyula N, Chen Z, Herter-Sprie GS, Cornell L, et al. Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway in KRAS-mutant non-small cell lung cancer. Oncotarget. 2018;9:31572–89.
de Leeuw R, McNair C, Schiewer MJ, Neupane NP, Brand LJ, Augello MA, et al. MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer. Clin Cancer Res. 2018;24:4201–14.
Romano G, Chen PL, Song P, McQuade JL, Liang RJ, Liu M, et al. A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling. Cancer Disco. 2018;8:556–67.
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.
Zhang J, Xu K, Liu PD, Geng Y, Wang B, Gan WJ, et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol Cell. 2017;62:929–42.
Knudsen ES, Kumarasamy V, Ruiz A, Sivinski J, Chung SJ, Grant A, et al. Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene. 2019;38:3355–70.
Michaloglou C, Crafter C, Siersbaek R, Delpuech O, Curwen JO, Carnevalli LS, 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;17:908–20.
Olmez I, Zhang Y, Manigat L, Benarmar M, Brenneman B, Nakano I, et al. Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in glioblastoma. Cancer Res. 2018;78:4360–9.
Ji WF, Shi YQ, Wang X, He WW, Tang L, Tian SW, et al. Combined androgen receptor blockade overcomes the resistance of breast cancer cells to palbociclib. Int J Biol Sci. 2019;15:522–32.
Li ZQ, Razavi P, Li Q, Toy WY, Liu B, Ping C, et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell. 2018;34:893–905.
Li F, Xu Y, Liu B, Singh PK, Zhao W, Jin JK, et al. YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer – Rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal cancer. Clin Cancer Res. 2019;25:2264–77.
Castellarnau MT, Atauri PD, Celada JT, Perarnau J, Yuneva M, Thomson TM, et al. De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition. Mol Syst Biol. 2017;13:940–55.
Qie S, Yoshida A, Parnharm S, Oleinik N, Beeson GC, Beeson CC, et al. Targeting glutamine-addiction and overcoming CDK4/6 inhibitor resistance in human esophageal squamous cell carcinoma. Nat Commun. 2019;10:1–15.
Kettner NM, Vijayarahavan S, Durak MG, Bui T, Kohansal M, Ha MJ, et al. Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer. Clin Cancer Res. 2019;25:3996–4013.
Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82.
Zhang JF, Bu X, Wang HZ, Zhu YS, Geng Y, Tan YY, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via Cul3 SPOP to control cancer immune surveillance. Nature. 2018;553:91–5.
Jin X, Ding DL, Yan YQ, Li H, Wang B, Ma LL, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-κB activation and PD-L1 expression. Mol Cell. 2019;73:22–35.
Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumor immunity. Nature. 2017;548:471–5.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (No. 81773754 to Ling Ding).
Author information
Authors and Affiliations
Contributions
XQX drafted the manuscript. XHP, TTW, JW, and BY critically revised the manuscript. LD and QJH designed the article. All authors have read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Xu, Xq., Pan, Xh., Wang, Tt. et al. Intrinsic and acquired resistance to CDK4/6 inhibitors and potential overcoming strategies. Acta Pharmacol Sin 42, 171–178 (2021). https://doi.org/10.1038/s41401-020-0416-4
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41401-020-0416-4
Keywords
This article is cited by
-
Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition
BMC Cancer (2025)
-
Single-cell RNA sequencing identifies molecular biomarkers predicting late progression to CDK4/6 inhibition in patients with HR+/HER2- metastatic breast cancer
Molecular Cancer (2025)
-
CDK4/6 inhibitors upregulate cIAP1/2, and Smac mimetic LCL161 enhances their antitumor effects in cholangiocarcinoma cells
Scientific Reports (2025)
-
A prognostic signature for hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer
Scientific Reports (2025)
-
Was kommt nach CDK4/6-Inhibition? Perspektiven beim fortgeschrittenen Mammakarzinom
Wiener klinische Wochenschrift (2025)
