cancer: Key mechanisms of response and failure.Oncogene
29 , 4018–4032 (2010). doi:10.1038/onc.2010.154;
pmid: 20473330- J. Lukas, J. Bartkova, M. Rohde, M. Strauss, J. Bartek, Cyclin
D1 is dispensable for G1 control in retinoblastoma gene-
deficient cells independently of cdk4 activity.Mol. Cell. Biol.
15 , 2600–2611 (1995). doi:10.1128/MCB.15.5.2600;
pmid: 7739541 - J. Lukaset al., Retinoblastoma-protein-dependent cell-cycle
inhibition by the tumour suppressor p16.Nature 375 ,
503 – 506 (1995). doi:10.1038/375503a0; pmid: 7777060 - R. H. Medema, R. E. Herrera, F. Lam, R. A. Weinberg, Growth
suppression by p16ink4 requires functional retinoblastoma
protein.Proc. Natl. Acad. Sci. U.S.A. 92 , 6289–6293 (1995).
doi:10.1073/pnas.92.14.6289; pmid: 7603984 - X. Gonget al., Genomic Aberrations that Activate D-type
Cyclins Are Associated with Enhanced Sensitivity to the
CDK4 and CDK6 Inhibitor Abemaciclib.Cancer Cell 32 ,
761 – 776.e6 (2017). doi:10.1016/j.ccell.2017.11.006;
pmid: 29232554 - S. Kimet al., The potent and selective cyclin-dependent
kinases 4 and 6 inhibitor ribociclib (LEE011) is a versatile
combination partner in preclinical cancer models.Oncotarget
9 , 35226–35240 (2018). doi:10.18632/oncotarget.26215;
pmid: 30443290 - J. E. Bisi, J. A. Sorrentino, P. J. Roberts, F. X. Tavares,
J. C. Strum, Preclinical Characterization of G1T28: A Novel
CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced
Myelosuppression.Mol. Cancer Ther. 15 , 783–793 (2016).
doi:10.1158/1535-7163.MCT-15-0775; pmid: 26826116 - J. Raderet al., Dual CDK4/CDK6 inhibition induces cell-cycle
arrest and senescence in neuroblastoma.Clin. Cancer Res.
19 , 6173–6182 (2013). doi:10.1158/1078-0432.CCR-13-1675;
pmid: 24045179 - R. Torres-Guzmánet al., Preclinical characterization of
abemaciclib in hormone receptor positive breast cancer.
Oncotarget 8 , 69493–69507 (2017). doi:10.18632/
oncotarget.17778; pmid: 29050219 - K. Michaudet al., Pharmacologic inhibition of cyclin-
dependent kinases 4 and 6 arrests the growth of glioblastoma
multiforme intracranial xenografts.Cancer Res. 70 , 3228– 3238
(2010). doi:10.1158/0008-5472.CAN-09-4559; pmid: 20354191 - T. J. Raubet al., Brain Exposure of Two Selective Dual
CDK4 and CDK6 Inhibitors and the Antitumor Activity of
CDK4 and CDK6 Inhibition in Combination with
Temozolomide in an Intracranial Glioblastoma Xenograft.
Drug Metab. Dispos. 43 , 1360–1371 (2015). doi:10.1124/
dmd.114.062745; pmid: 26149830 - F. Longet al., Preclinical characterization of SHR6390, a
novel CDK 4/6 inhibitor, in vitro and in human tumor
xenograft models.Cancer Sci. 110 , 1420–1430 (2019).
doi:10.1111/cas.13957; pmid: 30724426 - S. Linet al., FCN-437: A novel, potent and selective oral
inhibitor of CDK4/6 for the treatment of solid tumors.Cancer
Res. 79 (suppl. 13), 4425 (2019). doi:10.1158/1538-7445.
AM2019-4425 - L. Yinet al., A highly potent CDK4/6 inhibitor was rationally
designed to overcome blood brain barrier in gliobastoma
therapy.Eur. J. Med. Chem. 144 ,1–28 (2018). doi:10.1016/
j.ejmech.2017.12.003; pmid: 29247857 - C. Rubioet al., CDK4/6 Inhibitor as a Novel Therapeutic
Approach for Advanced Bladder Cancer Independently of
RB1Status.Clin. Cancer Res. 25 , 390–402 (2019).
doi:10.1158/1078-0432.CCR-18-0685; pmid: 30242024 - D. L. Burkhart, J. Sage, Cellular mechanisms of tumour
suppression by the retinoblastoma gene.Nat. Rev. Cancer
8 , 671–682 (2008). doi:10.1038/nrc2399;
pmid: 18650841 - A. Smirnovet al., FOXM1 regulates proliferation, senescence
and oxidative stress in keratinocytes and cancer cells.
Aging 8 , 1384–1397 (2016). doi:10.18632/aging.100988;
pmid: 27385468 - S. Vijayaraghavanet al., CDK4/6 and autophagy inhibitors
synergistically induce senescence in Rb positive cytoplasmic
cyclin E negative cancers.Nat. Commun. 8 , 15916 (2017).
doi:10.1038/ncomms15916; pmid: 28653662 - A. Yoshida, E. K. Lee, J. A. Diehl, Induction of Therapeutic
Senescence in Vemurafenib-Resistant Melanoma by
Extended Inhibition of CDK4/6.Cancer Res. 76 , 2990– 3002
(2016). doi:10.1158/0008-5472.CAN-15-2931;
pmid: 26988987 - M. Kovatchevaet al., MDM2 turnover and expression of ATRX
determine the choice between quiescence and senescence in
response to CDK4 inhibition.Oncotarget 6 , 8226– 8243
(2015). doi:10.18632/oncotarget.3364; pmid: 25803170- M. E. Kleinet al., PDLIM7 and CDH18 regulate the turnover of
MDM2 during CDK4/6 inhibitor therapy-induced senescence.
Oncogene 37 , 5066–5078 (2018). doi:10.1038/s41388-018-
0332-y; pmid: 29789718 - W. R. Wiedemeyeret al., Pattern of retinoblastoma pathway
inactivation dictates response to CDK4/6 inhibition in GBM.
Proc. Natl. Acad. Sci. U.S.A. 107 , 11501–11506 (2010).
doi:10.1073/pnas.1001613107; pmid: 20534551 - S. R. S. Gottesmanet al., Tyrosine Phosphorylation of
p27Kip1 Correlates with Palbociclib Responsiveness in Breast
Cancer Tumor Cells Grown in Explant Culture.
Mol. Cancer Res. 17 , 669–675 (2019). doi:10.1158/
1541-7786.MCR-18-0188; pmid: 30559257 - E. Raspéet al., CDK4 phosphorylation status and a linked
gene expression profile predict sensitivity to palbociclib.
EMBO Mol. Med. 9 , 1052–1066 (2017). doi:10.15252/
emmm.201607084; pmid: 28566333 - R. S. Finnet 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. 16 ,
25 – 35 (2015). doi:10.1016/S1470-2045(14)71159-3;
pmid: 25524798 - R. S. Finnet al., Biomarker Analyses of Response to
Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine
Therapy in Women with Treatment-Naïve Metastatic Breast
Cancer.Clin. Cancer Res. 26 , 110–121 (2020). doi:10.1158/
1078-0432.CCR-19-0751; pmid: 31527167 - N. C. Turneret al., Cyclin E1 Expression and Palbociclib
Efficacy in Previously Treated Hormone Receptor-Positive
Metastatic Breast Cancer.J. Clin. Oncol. 37 , 1169– 1178
(2019). doi:10.1200/JCO.18.00925; pmid: 30807234 - Z. Liet al., Loss of the FAT1 Tumor Suppressor Promotes
Resistance to CDK4/6 Inhibitors via the Hippo Pathway.
Cancer Cell 34 , 893–905.e8 (2018). doi:10.1016/
j.ccell.2018.11.006; pmid: 30537512 - M. Cheng, V. Sexl, C. J. Sherr, M. F. Roussel, Assembly of
cyclin D-dependent kinase and titration of p27Kip1 regulated
by mitogen-activated protein kinase kinase (MEK1).
Proc. Natl. Acad. Sci. U.S.A. 95 , 1091–1096 (1998).
doi:10.1073/pnas.95.3.1091; pmid: 9448290 - E. A. Klein, R. K. Assoian, Transcriptional regulation of the
cyclin D1 gene at a glance.J. Cell Sci. 121 , 3853– 3857
(2008). doi:10.1242/jcs.039131; pmid: 19020303 - J. N. Lavoie, G. L’Allemain, A. Brunet, R. Müller, J. Pouysségur,
Cyclin D1 expression is regulated positively by the p42/
p44MAPK and negatively by the p38/HOGMAPK pathway.
J. Biol. Chem. 271 , 20608–20616 (1996). doi:10.1074/
jbc.271.34.20608; pmid: 8702807 - J. Lukas, J. Bartkova, J. Bartek, Convergence of mitogenic
signalling cascades from diverse classes of receptors at the
cyclin D-cyclin-dependent kinase-pRb-controlled G1
checkpoint.Mol. Cell. Biol. 16 , 6917–6925 (1996).
doi:10.1128/MCB.16.12.6917; pmid: 8943347 - R. C. Muise-Helmerickset al., Cyclin D expression is
controlled post-transcriptionally via a phosphatidylinositol
3-kinase/Akt-dependent pathway.J. Biol. Chem. 273 ,
29864 – 29872 (1998). doi:10.1074/jbc.273.45.29864;
pmid: 9792703 - M. Peket al., Oncogenic KRAS-associated gene signature
defines co-targeting of CDK4/6 and MEK as a viable
therapeutic strategy in colorectal cancer.Oncogene 36 ,
4975 – 4986 (2017). doi:10.1038/onc.2017.120;
pmid: 28459468 - S. R. Voraet al., CDK 4/6 inhibitors sensitize PIK3CA mutant
breast cancer to PI3K inhibitors.Cancer Cell 26 , 136– 149
(2014). doi:10.1016/j.ccr.2014.05.020; pmid: 25002028 - C. A. Martinet al., Palbociclib synergizes with BRAF and
MEK inhibitors in treatment naïve melanoma but not after
the development of BRAF inhibitor resistance.Int. J.
Cancer 142 , 2139–2152 (2018). doi:10.1002/ijc.31220;
pmid: 29243224 - J. L. F. Tehet al.,In VivoE2F Reporting Reveals Efficacious
Schedules of MEK1/2-CDK4/6 Targeting and mTOR-S6
Resistance Mechanisms.Cancer Discov. 8 , 568–581 (2018).
doi:10.1158/2159-8290.CD-17-0699; pmid: 29496664 - A. Dall’Acquaet al., CDK6 protects epithelial ovarian cancer
from platinum-induced death via FOXO3 regulation.
EMBO Mol. Med. 9 , 1415–1433 (2017). doi:10.15252/
emmm.201607012; pmid: 28778953
92. H. Gaoet al., High-throughput screening using patient-
derived tumor xenografts to predict clinical trial drug
response.Nat. Med. 21 , 1318–1325 (2015). doi:10.1038/
nm.3954; pmid: 26479923
93. V. Yadavet al., The CDK4/6 inhibitor LY2835219 overcomes
vemurafenib resistance resulting from MAPK reactivation
and cyclin D1 upregulation.Mol. Cancer Ther. 13 , 2253– 2263
(2014). doi:10.1158/1535-7163.MCT-14-0257;
pmid: 25122067
94. A. C. Woodet al., DualALKandCDK4/6Inhibition
Demonstrates Synergy against Neuroblastoma.Clin. Cancer
Res. 23 , 2856–2868 (2017). doi:10.1158/1078-0432.CCR-16-
1114 ; pmid: 27986745
95. S. Goelet al., Overcoming Therapeutic Resistance in
HER2-Positive Breast Cancers with CDK4/6 Inhibitors.
Cancer Cell 29 , 255–269 (2016). doi:10.1016/
j.ccell.2016.02.006; pmid: 26977878
96. J. L. Dean, A. K. McClendon, E. S. Knudsen, Modification of
the DNA damage response by therapeutic CDK4/6 inhibition.
J. Biol. Chem. 287 , 29075–29087 (2012). doi:10.1074/
jbc.M112.365494; pmid: 22733811
97. Y. Pikmanet al., Synergistic Drug Combinations with a
CDK4/6 Inhibitor in T-cell Acute Lymphoblastic Leukemia.
Clin. Cancer Res. 23 , 1012–1024 (2017). doi:10.1158/
1078-0432.CCR-15-2869; pmid: 28151717
98. J. Caoet al., Combining CDK4/6 inhibition with taxanes
enhances anti-tumor efficacy by sustained impairment of
pRB-E2F pathways in squamous cell lung cancer.Oncogene
38 , 4125–4141 (2019). doi:10.1038/s41388-019-0708-7;
pmid: 30700828
99. Y. Gaoet al., Inhibition of CDK4 sensitizes multidrug resistant
ovarian cancer cells to paclitaxel by increasing apoptosiss.
Cell Oncol. 40 , 209–218 (2017). doi:10.1007/
s13402-017-0316-x; pmid: 28243976
100. B. Salvador-Barberoet al., CDK4/6 Inhibitors Impair
Recovery from Cytotoxic Chemotherapy in Pancreatic
Adenocarcinoma.Cancer Cell 37 , 340–353.e6 (2020).
doi:10.1016/j.ccell.2020.01.007; pmid: 32109375
101. J. Yiet al., MYC status as a determinant of synergistic
response to Olaparib and Palbociclib in ovarian cancer.
EBioMedicine 43 , 225–237 (2019). doi:10.1016/
j.ebiom.2019.03.027; pmid: 30898650
102. D. Tempkaet al., Downregulation of PARP1 transcription by
CDK4/6 inhibitors sensitizes human lung cancer cells to
anticancer drug-induced death by impairing OGG1-dependent
base excision repair.Redox Biol. 15 , 316–326 (2018).
doi:10.1016/j.redox.2017.12.017; pmid: 29306194
103. S. M. Johnsonet al., Mitigation of hematologic radiation
toxicity in mice through pharmacological quiescence induced
by CDK4/6 inhibition.J. Clin. Invest. 120 , 2528–2536 (2010).
doi:10.1172/JCI41402; pmid: 20577054
104. S. Heet al., Transient CDK4/6 inhibition protects
hematopoietic stem cells from chemotherapy-induced
exhaustion.Sci. Transl. Med. 9 , eaal3986 (2017).
doi:10.1126/scitranslmed.aal3986; pmid: 28446688
105. J. M. Weisset al., Myelopreservation with the CDK4/6
inhibitor trilaciclib in patients with small-cell lung cancer
receiving first-line chemotherapy: A phase Ib/randomized
phase II trial.Ann. Oncol. 30 , 1613–1621 (2019). doi:10.1093/
annonc/mdz278; pmid: 31504118
106. A. R. Tanet 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. 20 , 1587– 1601
(2019). doi:10.1016/S1470-2045(19)30616-3;
pmid: 31575503
107. J. O’Shaughnessyet al.,“Trilaciclib improves overall survival
when given with gemcitabine/carboplatin in patients with
metastatic triple-negative breast cancer.”Paper presented at
the 2020 San Antonio Breast Cancer Symposium, abstract
PD1-06 (2020).
108. J. Franco, U. Balaji, E. Freinkman, A. K. Witkiewicz,
E. S. Knudsen, Metabolic Reprogramming of Pancreatic
Cancer Mediated by CDK4/6 Inhibition Elicits Unique
Vulnerabilities.Cell Rep. 14 , 979–990 (2016). doi:10.1016/
j.celrep.2015.12.094; pmid: 26804906
109. Q. Yinet al., CDK4/6 regulate lysosome biogenesis through
TFEB/TFE3.J. Cell Biol. 219 , e201911036 (2020).
doi:10.1083/jcb.201911036; pmid: 32662822
110. L. Martínez-Carrereset al., CDK4 Regulates Lysosomal
Function and mTORC1 Activation to Promote Cancer Cell
Survival.Cancer Res. 79 , 5245–5259 (2019). doi:10.1158/
0008-5472.CAN-19-0708; pmid: 31395606
Fasslet al.,Science 375 , eabc1495 (2022) 14 January 2022 18 of 19
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