7,347
Views
14
CrossRef citations to date
0
Altmetric
Review

The evolution of cyclin dependent kinase inhibitors in the treatment of cancer

, , , , , , , , , & show all
Pages 1105-1124 | Received 11 Feb 2021, Accepted 07 Jun 2021, Published online: 01 Sep 2021

References

  • Woo RA, Poon RY. Cyclin-dependent kinases and S phase control in mammalian cells. Cell Cycle. 2003;2(4):316–324.
  • Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 2005;30(11):630–641.
  • Cerqueira A, Martín A, Symonds CE, et al. Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors. Mol Cell Biol. 2014;34(8):1452–1459.
  • Cobrinik D. Pocket proteins and cell cycle control. Oncogene. 2005;24(17):2796–2809.
  • Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer. 2008;8(9):671–682.
  • De Boer L, Oakes V, Beamish H, et al. Cyclin A/cdk2 coordinates centrosomal and nuclear mitotic events. Oncogene. 2008;27(31):4261–4268.
  • De Souza CP, Ellem KA, Gabrielli BG. Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events. Exp Cell Res. 2000;257(1):11–21.
  • LaPak KM, Burd CE. The molecular balancing act of p16(INK4a) in cancer and aging. Mol Cancer Res. 2014;12(2):167–183.
  • Narasimha AM, Kaulich M, Shapiro GS, et al. Cyclin D activates the Rb tumor suppressor by mono-phosphorylation. Elife. 2014;3:3.
  • Siu KT, Rosner MR, Minella AC. An integrated view of cyclin E function and regulation. Cell Cycle. 2012;11(1):57–64.
  • George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47–53.
  • Liu J, Lichtenberg T, Hoadley KA, et al. An integrated TCGA Pan-Cancer clinical data resource to drive high-Quality survival outcome analytics. Cell. 2018;173(2):400–416.e411.
  • Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321–337.e310.
  • Binh MB, Sastre-Garau X, Guillou L, et al. MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol. 2005;29(10):1340–1347.
  • Sirvent N, Coindre JM, Maire G, et al. Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples: utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR. Am J Surg Pathol. 2007;31(10):1476–1489.
  • Appay R, Dehais C, Maurage C-A, et al. CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol. 2019;21(12):1519–1528.
  • Tam KW, Zhang W, Soh J, et al. CDKN2A/p16 inactivation mechanisms and their relationship to smoke exposure and molecular features in non-small-cell lung cancer. J Thorac Oncol. 2013;8(11):1378–1388.
  • Aftab A, Shahzad S, Hussain HMJ, et al. CDKN2A/P16INK4A variants association with breast cancer and their in-silico analysis. Breast Cancer. 2019;26(1):11–28.
  • Bhateja P, Chiu M, Wildey G, et al. Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer. Cancer Med. 2019;8(4):1459–1466.
  • Lundberg A, Lindström LS, Li J, et al. The long-term prognostic and predictive capacity of cyclin D1 gene amplification in 2305 breast tumours. Breast Cancer Res. 2019;21(1):34.
  • Petersen S, Wilson AJ, Hirst J, et al. CCNE1 and BRD4 co-amplification in high-grade serous ovarian cancer is associated with poor clinical outcomes. Gynecol Oncol. 2020;157(2):405–410.
  • Zhao ZM, Yost SE, Hutchinson KE, et al. CCNE1 amplification is associated with poor prognosis in patients with triple negative breast cancer. BMC Cancer. 2019;1(1):96.
  • Asghar U, Witkiewicz AK, Turner NC, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–146.
  • Awan FT, Jones JA, Maddocks K, et al. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy. Ann Hematol. 2016;95(7):1137–1143.
  • Parry D, Guzi T, Shanahan F, et al. Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor. Mol Cancer Ther. 2010;9(8):2344–2353.
  • Nemunaitis JJ, Small KA, Kirschmeier P, et al. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11(1):259.
  • Mita MM, Mita AC, Moseley JL, et al. Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin-dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies. Br J Cancer. 2017;117(9):1258–1268.
  • Johnson SF, Cruz C, Greifenberg AK, et al. CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep. 2016;17(9):2367–2381.
  • Horiuchi D, Kusdra L, Huskey NE, et al. MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition. J Exp Med. 2012;209(4):679–696.
  • Rajput S, Khera N, Guo Z, et al. Inhibition of cyclin dependent kinase 9 by dinaciclib suppresses cyclin B1 expression and tumor growth in triple negative breast cancer. Oncotarget. 2016;7(35):56864–56875.
  • Hossain DMS, Javaid S, Cai M, et al. Dinaciclib induces immunogenic cell death and enhances anti-PD1-mediated tumor suppression. J Clin Invest. 2018;128(2):644–654.
  • Chien AJ, Gliwa AS, Rahmaputri S, et al. A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC) and response correlation with MYC-overexpression. J Clin Oncol. 2020;38(15_suppl):1076.
  • Mita MM, Joy AA, Mita A, et al. Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus capecitabine in patients with advanced breast cancer. Clin Breast Cancer. 2014;14(3):169–176.
  • Stephenson JJ, Nemunaitis J, Joy AA, et al. Randomized phase 2 study of the cyclin-dependent kinase inhibitor dinaciclib (MK-7965) versus erlotinib in patients with non-small cell lung cancer. Lung Cancer. 2014;83(2):219–223.
  • Cidado J, Boiko S, Proia T, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. 2020;26(4):922–934.
  • Torres-Guzmán R, Calsina B, Hermoso A, et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget. 2017;8(41):69493–69507.
  • Leonard JP, LaCasce AS, Smith MR, et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012;119(20):4597–4607.
  • Bagegni N, Thomas S, Liu N, et al. Serum thymidine kinase 1 activity as a pharmacodynamic marker of cyclin-dependent kinase 4/6 inhibition in patients with early-stage breast cancer receiving neoadjuvant palbociclib. Breast Cancer Res. 2017;19(1):123.
  • 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(1):25–35.
  • Finn RS, Martin M, Rugo HS, et al., Palbociclib and Letrozole in advanced breast cancer. N Engl J Med. 375(20): 1925–1936. 2016.
  • Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-Line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738–1748.
  • Tripathy D, Im SA, Colleoni M, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 2018;19(7):904–915.
  • Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638–3646.
  • Sledge GW Jr., 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(25):2875–2884.
  • Slamon DJ, Neven P, Chia S, et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3. J Clin Oncol. 2018;36(24):2465–2472.
  • Crostfanilli 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(4):425–439.
  • 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(17):5218–5224.
  • Gao JJ, Cheng J, Bloomquist E, et al. CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US food and drug administration pooled analysis. Lancet Oncol. 2020;21(2):250–260.
  • Hamilton EP, Cortés J, Ozyilkan O, et al. 273O nextMONARCH: final overall survival analysis of abemaciclib monotherapy or in combination with tamoxifen in patients with HR+, HER2- metastatic breast cancer. Ann Oncol. 2020;31:S348.
  • Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB) [Abstract LBA7PR]. Ann Oncol. 2019;30(suppl 5):v856–v934.
  • Sledge GW Jr, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial. JAMA Oncol. 2019;6(1):116–124.
  • Turner NC, Slamon DJ, Ro J, et al. Overall survival with Palbociclib and Fulvestrant in advanced breast cancer. N Engl J Med. 2018;379(20):1926–1936.
  • Lynce F, Saleh M, Shajahan-Haq A, et al. PALINA: a phase II safety study of palbociclib in combination with letrozole or fulvestrant in African American women with hormone receptor positive HER2 negative advanced breast cancer. Contemp Clin Trials Commun. 2018;10:190–192.
  • Patnaik A, Rosen LS, Tolaney SM, 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(7):740–753.
  • Johnston SRD, Harbeck N, Hegg R, et al. LBA5_PR Abemaciclib in high risk early breast cancer. Ann Oncol. 2020;31:S1143–S1144.
  • Mayer EL, Gnant MI, DeMichele A, et al. PALLAS: a randomized phase III trial of adjuvant palbociclib with endocrine therapy versus endocrine therapy alone for HR+/HER2- early breast cancer. Ann Oncol. 2020;31(4):LBA12.
  • Pfizer Inc. Penelope-B trial of Ibrance® (palbociclib) in early breast cancer did not meet primary endpoint. 2020 [2020 Oct 9). [ cited 2020 Nov 12]. Available from: https://www.pfizer.com/news/press-release/press-release-detail/penelope-b-trial-ibrancer-palbociclib-early-breast-cancer.
  • Pajic M, Froio D, Daly S, et al. miR-139-5p modulates radtherapy resistance in breast cancer by repressing multiple gene networks of DNA repair and ROS defense. Cancer Res. 2018;78(2):501–515.
  • Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer. Clin Cancer Res. 2017;23(15):4055.
  • Cottu P, D’Hondt V, Dureau S, et al. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018;29(12):2334–2340.
  • Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997–3005.
  • Albanell J, Martinez MTM, Ramos M, et al. LBA19 GEICAM/2014-12 (FLIPPER) study: first analysis from a randomized phase II trial of fulvestrant (F)/palbociclib (P) versus (vs) F/placebo (PL) as first-line therapy in postmenopausal women with HR (hormone receptor)+/HER2– endocrine sensitive advanced breast cancer (ABC). Ann Oncol. 2020;31:S1151.
  • Llombart-Cussac A, Pérez-García JM, Bellet M, et al. PARSIFAL: a randomized, multicenter, open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer [Abstract]. J Clin Oncol. 2020;38(Suppl):1007.
  • Bidard F-C, Pistilli B, Dalenc F, et al. Circulating ESR1 mutation detection rate and early decrease under first line aromatase inhibitor and palbociclib in the PADA-1 trial. Cancer Res. 2019;79(4 suppl): PD2–06.
  • Bidard FC, Callens C, Dalenc F, et al. Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: an exploratory analysis of the PADA-1 trial. J clin oncol. 2020;38(15_suppl):1010.
  • DeMichele A, Clark AS, Tan KS, et al. CDK 4/6 Inhibitor Palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21(5):995–1001.
  • Infante JR, Cassier PA, Gerecitano JF, et al. A phase I Study of the Cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin Cancer Res. 2016;22(23):5696–5705.
  • Sriman S, Anita S, Somedeb B, et al. CLO19-051: CDK 4/6 inhibitor-associated hematologic toxicities and febrile neutropenia in patients with hormone receptor-positive HER2-negative metastatic breast cancer. J Natl Compr Canc Netw. 2019;17(3.5). doi: https://doi.org/10.6004/jnccn.2018.7152
  • Verma S, Bartlett CH, Schnell P, et al. Palbociclib in combination with fulvestrant in women with hormone receptor-positive/HER2-negative advanced metastatic breast cancer: detailed safety analysis from a multicenter, randomized, placebo-controlled, phase III study (PALOMA-3). The Oncologist. 2016;21(10):1165–1175.
  • Rugo HS, Mayer E, Storniolo AM, et al. Palbociclib in combination with fulvestrant or tamoxifen as treatment for hormone receptor positive metastatic breast cancer with prior chemotherapy for advanced disease (TBCRC 035): a Phase II study with pharmacodynamic markers [Abstract]. Cancer Res. 2019;79(13 suppl):CT128.
  • Sun W, O’Dwyer PJ, Finn RS, et al. Characterization of neutropenia in advanced cancer patients following palbociclib treatment using a population pharmacokinetic-pharmacodynamic modeling and simulation approach. J Clin Pharmacol. 2017;57(9):1159–1173.
  • Howie LJ, Singh H, Bloomquist E, et al. Outcomes of older women with hormone receptor–positive, human epidermal growth factor receptor–negative metastatic breast cancer treated with a CDK4/6 inhibitor and an aromatase inhibitor: an FDA pooled analysis. J Clin Oncol. 2019;37(36):3475–3483.
  • Petrelli F, Ghidini A, Pedersini R, et al. Comparative efficacy of palbociclib, ribociclib and abemaciclib for ER+ metastatic breast cancer: an adjusted indirect analysis of randomized controlled trials. Breast Cancer Res Treat. 2019;174(3):597–604.
  • Thibault S, Hu W, Hirakawa B, et al. Intestinal toxicity in rats following administration of CDK4/6 inhibitors is independent of primary pharmacology. Mol Cancer Ther. 2019;18(2):257.
  • Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541–1547.
  • 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):17.
  • Gervaso L, Montero AJ, Jia X, et al. Venous thromboembolism in breast cancer patients receiving cyclin-dependent kinase inhibitors. J Thromb Haemost. 2020;18(1):162–168.
  • Chappell JC, Turner PK, Pak YA, et al. Abemaciclib inhibits renal tubular secretion without changing glomerular filtration rate. Clin Pharmacol Ther. 2019;105(5):1187–1195.
  • Novartis. Kisquali (ribociclib) prescribing information. 2017 [ last update: Mar 2017]). [ cited 2020 Sep 11]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf.
  • US Food and Drug Administration, FDA Drug Safety Communication. FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer. 2019 [ last update: 2019 Sep 13]). [ cited 2020 Sep 11]. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-severe-lung-inflammation-ibrance-kisqali-and-verzenio-breast-cancer.
  • Thill M, Schmidt M. Management of adverse events during cyclin-dependent kinase 4/6 (CDK4/6) inhibitor-based treatment in breast cancer. Ther Adv Med Oncol. 2018;10:1758835918793326.
  • Finn R, Jiang Y, Rugo H, et al. Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER + /HER2– advanced breast cancer (ABC). Ann Oncol. 2016;27(suppl 6):V1554.
  • Finn RS, Liu Y, Zhu Z, et al. Biomarker analyses of response to cyclin dependent kinase 4/6 inhibition and endocrine therapy in women with treatment-naive metastatic breast cancer. Clin Cancer Res. 2019. 2019/09/19 [Epub ahead of print]. doi: https://doi.org/10.1158/1078-0432.Ccr-19-0751
  • Bardia A, Colleoni M, Campos-Gomez S, et al. Ribociclib with endocrine therapy for premenopausal patients with hormone receptor-positive, HER2-negative advanced breast cancer: biomarker analyses from the phase III randomized MONALEESA-7 trial [Abstract]. Cancer Res. 2019;79(4 suppl): PD2–08.
  • Tolaney SM, Cortes J, Dickler MN, et al. Exploratory biomarkers in MONARCH 1, a phase II study of abemaciclib monotherapy in hormone-receptor positive (HR) HER2- metastatic breast cancer (MBC). Ann Oncol. 2016;27:vi552.
  • 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(3):640–645.
  • O’Leary B, Cutts RJ, Liu Y, et al., The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 8(11): 1390–1403. 2018.
  • Wander SA, Cohen O, Gong X, et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor positive metastatic breast cancer. Cancer Discov. 2020 May 15;10(8):1174–1193. [Epub ahead of print].
  • Gong X, Du J, Parsons SH, et al. Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene. Cancer Discov. 2019;9(2):248.
  • Li Z, Razavi P, Li Q, et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 Inhibitors via the Hippo Pathway. Cancer Cell. 2018;34(6):893–905.e898.
  • Yang C, Li Z, Bhatt T, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene. 2017;36(16):2255–2264.
  • Cornell L, Wander SA, Visal T, et al. MicroRNA-mediated suppression of the TGF-beta pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep. 2019;26(10):2667–2680.e2667.
  • Brand M, Jiang B, Bauer S, et al. Homolog-Selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem Biol. 2019;26(2):300–306 e309.
  • Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478(7370):529–533.
  • Turner NC, Liu Y, Zhu Z, et al. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor–positive metastatic breast cancer. J Clin Oncol. 2019;37(14):1169–1178.
  • Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76(8):2301–2313.
  • Hu B, Mitra J, van den Heuvel S, et al. S and G2 phase roles for Cdk2 revealed by inducible expression of a dominant-negative mutant in human cells. Mol Cell Biol. 2001;21(8):2755–2766.
  • Caldon CE, Sergio CM, Kang J, et al. Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. 2012;11(7):1488–1499.
  • Geng Y, Lee YM, Welcker M, et al. Kinase-independent function of cyclin E. Mol Cell. 2007;25(1):127–139.
  • L’Italien L, Tanudji M, Russell L, et al. Unmasking the redundancy between Cdk1 and Cdk2 at G2 phase in human cancer cell lines. Cell Cycle. 2006;5(9):984–993.
  • Cai D, Latham VM Jr., Zhang X, et al. Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res. 2006;66(18):9270–9280.
  • Larochelle S, Pandur J, Fisher RP, et al. CDK7 is essential for mitosis and for in vivo CDK-activating kinase activity. Genes Dev. 1998;12(3):370–381.
  • Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770–1783.
  • Chen YN, Sharma SK, Ramsey TM, et al. Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A. 1999;96(8):4325–4329.
  • Gralewska P, Gajek A, Marczak A, et al. Participation of the ATR/CHK1 pathway in replicative stress targeted therapy of high-grade ovarian cancer. 2020 Apr 21 [cited 2020 Sep 17]; doi: https://doi.org/10.1186/s13045-020-00874-6.
  • Parmar K, Kochupurakkal BS, Lazaro JB, et al. The CHK1 inhibitor prexasertib exhibits monotherapy activity in high-grade serous ovarian cancer models and sensitizes to PARP inhibition. Clin Cancer Res. 2019;25(20):6127–6140.
  • Lee JM, Nair J, Zimmer A, et al. Prexasertib, a cell cycle checkpoint kinase 1 and 2 inhibitor, in BRCA wild-type recurrent high-grade serous ovarian cancer: a first-in-class proof-of-concept phase 2 study. Lancet Oncol. 2018;19(2):207–215.
  • Formisano L, Lu Y, Servetto A, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10(1):1373.
  • Mayer IA, Haley BB, Abramson VG, et al. A phase Ib trial of fulvestrant + CDK4/6 inhibitor (CDK4/6i) palbociclib + pan-FGFR tyrosine kinase inhibitor (TKI) erdafitinib in FGFR-amplified/ ER+/HER2-negative metastatic breast cancer (MBC). Presented at the San Antonio Breast Cancer Symposium 2020 December 8-11. 2020;[ Epub ahead of print].
  • Haines E, Chen T, Kommajosyula N, 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(60):31572–31589.
  • de Leeuw R, McNair C, Schiewer MJ, et al. MAPK Reliance via Acquired CDK4/6 inhibitor resistance in cancer. Clin Cancer Res. 2018;24(17):4201–4214.
  • Shapiro GI, Hilton J, Gandi L, et al. Phase I dose escalation study of the CDK4/6 inhibitor palbociclib in combination with the MEK inhibitor PD-0325901 in patients with RAS mutant solid tumors [Abstract]. Cancer Res. 2017;77(13 suppl):CT046.
  • Costa C, Wang Y, Ly A, et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kalpha inhibitors in breast cancer. Cancer Discov. 2020;10(1):72–85.
  • Blain SW, Massagué J. Breast cancer banishes p27 from nucleus. Nature Med. 2002;8(10):1076–1078.
  • Jansen VM, Bhola NE, Bauer JA, 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(9):2488–2499.
  • Vora SR, Juric D, Kim N, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26(1):136–149.
  • Goel S, Wang Q, Watt AC, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 2016;29(3):255–269.
  • Martin M, Hurvitz SA, Chan D, et al. Final results of NeoMONARCH: a phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC) [Abstract]. Cancer Res. 2018;78(4 suppl): PD5–01.
  • Diehl JA, Cheng M, Roussel MF, et al. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998;12(22):3499–3511.
  • Bardia A, Hurvitz SA, DeMichele A, et al. Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): efficacy, safety, and biomarker results [Abstract]. J Clin Oncol. 2019;37(15 suppl):1016.
  • Bardia A, Hurvitz SA, DeMichele A, et al. Phase I/II trial of exemestane, ribociclib, and everolimus in women with HR+/HER2 advanced breast cancer after progression on CDK4/6 Inhibitors (TRINITI-1). Clin Cancer Res. 2021. Epub ahead of print. doi: https://doi.org/10.1158/1078-0432.CCR-20-2114.
  • Maiso P, Huynh D, Moschetta M, et al. Metabolic signature identifies novel targets for drug resistance in multiple myeloma. Cancer Res. 2015;75(10):2071–2082.
  • Tarrado-Castellarnau M, de Atauri P, Cascante M. Oncogenic regulation of tumor metabolic reprogramming. Oncotarget. 2016;7(38):62726–62753.
  • Tarrado-Castellarnau M, de Atauri P, Tarragó-Celada J, et al. De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition. Mol Syst Biol. 2017;13(10):940.
  • Hydbring P, Larsson LG. Tipping the balance: cdk2 enables Myc to suppress senescence. Cancer Res. 2010;70(17):6687–6691.
  • Hydbring P, Bahram F, Su Y, et al. Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc Nat Acad Sci. 2010;107(1):58.
  • Campaner S, Doni M, Hydbring P, et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol. 2010;12(1):54–59. sup pp 51-14.
  • Dauch D, Rudalska R, Cossa G, et al. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med. 2016;22(7):744–753.
  • Huang CH, Lujambio A, Zuber J, et al. CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma. Genes Dev. 2014;28(16):1800–1814.
  • Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–917.
  • Bisi JE, Sorrentino JA, Jordan JL, et al. Preclinical development of G1T38: a novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget. 2017;8(26):42343–42358.
  • Bulat I, Maglakelidze M, Murias C, et al. Dose escalation and expansion study of lerociclib (G1T38), an oral CDK4/6 inhibitor, dosed with no drug holiday in combination with fulvestrant in patints with HR+/HER2- advanced breast cancer [poster P1-19-17]. Presented at the San Antonio Breast Cancer Symposium. 2019 December 10-14; San Antonio, TX.
  • CStone Pharmaceuticals. CStone completes registration filing for the Phase I trial of CDK4/6 inhibitor CS3002 in Australia and will soon initiate the study [newswire]. 2019 [ last update: 2019 Aug 22]). [ cited 2020 Sep 14]. Available from: https://www.prnewswire.com/news-releases/cstone-completes-registration-filing-for-the-phase-i-trial-of-cdk46-inhibitor-cs3002-in-australia-and-will-soon-initiate-the-study-300906227.html.
  • Yu Q, Geng Y, Sicinski P. Specific protection against breast cancers by cyclin D1 ablation. Nature. 2001;411(6841):1017–1021.
  • Reddy HK, Mettus RV, Rane SG, et al. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis. Cancer Res. 2005;65(22):10174–10178.
  • Yu Q, Sicinska E, Geng Y, et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell. 2006;9(1):23–32.
  • ElChaarani B, Stires H, Pohlmann PR, et al. Pre-clinical analysis of the CDK4/6 inhibitor palbociclib in HER2-positive breast cancer [Abstract]. J Clin Oncol. 2017;35(15 suppl):e12520.
  • Goel S, Pernas S, Tan-Wasielewski Z, et al. Ribociclib plus trastuzumab in advanced HER2-positive breast cancer: results of a phase 1b/2 trial. Clin Breast Cancer. 2019;19(6):399–404.
  • Tolaney SM, Wardley AM, Zambelli S, et al. Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(6):763–775.
  • Ciruelos EM, Villagrasa P, Antunes De Melo e Oliveira AM, et al. Palbociclib, trastuzumab and endocrine therapy (ET) versus treatment of physician’s choice (TPC) in metastatic HER2-positive and hormone receptor-positive (HER2+/HR+) breast cancer (BC) with PAM50 luminal intrinsic subtype (SOLTI-1303 PATRICIA II): a randomized phase II trial. Annals of Oncology : Official Journal of the European Society for Medical Oncology. 2020;31(2): 180TiP.
  • Pascual T, Pernaut C, Tolosa P, et al. Abstract P2-08-17: tumor inflammation signature (TIS), intrinsic subtypes and chemo-endocrine score (CES) in metastatic triple-negative breast cancer (mTNBC): a SOLTI biomarker program study. Cancer Res. 2019;79(4Supplement): P2-08-17.
  • Shagisultanova E, Chalasani P, Brown-Glaberman UA, et al. Tucatinib, palbociclib, and letrozole in HR+/HER2+ metastatic breast cancer: report of phase IB safety cohort. J clin oncol. 2019;37(15_suppl):102.
  • Weiss JM, Csoszi T, Maglakelidze M, et 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. 2019;30(10):1613–1621.
  • 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.
  • 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(18):5561–5572.
  • Teo ZL, Versaci S, Dushyanthen S, et al. Combined CDK4/6 and PI3K alpha inhibition is synergistic and immunogenic in triple-negative breast cancer. Cancer Res. 2017;77(22):6340–6352.
  • Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–475.
  • Deng J, Wang ES, Jenkins RW, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216–233.
  • Schaer DA, Beckmann RP, Dempsey JA, et al. The CDK4/6 inhibitor Abemaciclib Induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep. 2018;22(11):2978–2994.
  • Herold CI, Trippa L, Li T, et al. A phase 1b study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with hormone receptor-positive metastatic breast cancer (HR+ MBC) and metastatic ovarian cancer (MOC) [abstract]. Cancer Res. 2020;80(4suppl): P3-14-03.
  • Galbraith MD, Bender H, Espinosa JM. Therapeutic targeting of transcriptional cyclin-dependent kinases. Transcription. 2019;10(2):118–136.
  • Patel H, Abduljabbar R, Lai C-F, et al. Expression of CDK7, cyclin H, and MAT1 is elevated in breast cancer and is prognostic in estrogen receptor–positive breast cancer. Clin Cancer Res. 2016;22(23):5929.
  • Hu S, Marineau JJ, Rajagopal N, et al. Discovery and Characterization of SY-1365, a selective, covalent inhibitor of CDK7. Cancer Res. 2019;79(13):3479–3491.
  • Martin LA, Pancholi S, Ribas R, et al. Resistance to palbociclib depends on multiple targetable mechanisms highlighting the potential of drug holidays and drug switching to improve therapeutic outcome [abstract P3-03-09]. Cancer Res. 2017;77: P3–03.
  • Guarducci C, Nardone A, Feiglin A, et al. Inhibition of CDK7 overcomes resistance to CDK4/6 inhibitors in hormone receptor positive breast cancer cells [abstract]. Cancer Res. 2019;79(4 suppl): PD7–12.
  • Sun B, Mason S, Wilson RC, et al. Inhibition of the transcriptional kinase CDK7 overcomes therapeutic resistance in HER2-positive breast cancers. Oncogene. 2020;39(1):50–63.
  • Do KT, Chau N, Wolanski A, et al. Abstract CT037: phase I safety, pharmacokinetic and pharmacodynamic study of CYC065, a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953). Cancer Res. 2018;78(13 Supplement):CT037.
  • Do KT, Frej K, Bhushan K, et al. Phase 1 safety, pharmacokinetic and pharmacodynamic study of fadraciclib (CYC065), a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953). Eur J Cancer. 2020;138:S7.
  • Frame S, Saladino C, MacKay C, et al. Fadraciclib (CYC065), a novel CDK inhibitor, targets key pro-survival and oncogenic pathways in cancer. PLoS One. 2020;15(7):e0234103.
  • Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle. 2016;15(4):519–527.