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Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors

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Abstract

Cyclin-dependent kinase (CDK) 4/6 inhibitors have emerged in the treatment of metastatic hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, most patients will eventually present disease progression, highlighting the inevitable resistance of cancer cells to CDK4/6 inhibition. Several studies have suggested that resistance mechanisms involve aberrations of the molecules that regulate the cell cycle, and the re-wiring of the cell to escape CDK4/6 dependence and turn to alternative pathways. Loss of retinoblastoma function, overexpression of CDK 6, upregulation of cyclin E, overexpression of CDK 7, and dysregulation of several signaling pathways, notably the PI3/AKT/mTOR pathway, have been implicated in the development of resistance to CDK4/6 inhibitors. Overlap with endocrine resistance mechanisms might be possible. Combinational therapeutic strategies should be explored in order to prevent resistance and optimize the management of patients after progression under CDK 4/6 inhibition.

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References

  1. Spring LM, Wander SA, Andre F, Moy B, Turner NC, Bardia A (2020) Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395(10226):817–827. https://doi.org/10.1016/S0140-6736(20)30165-3

    Article  CAS  PubMed  Google Scholar 

  2. Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F et al (2018) 4th ESO-ESMO international consensus guidelines for advanced breast Cancer (ABC 4)dagger. Ann Oncol Off J Eur Soc Med Oncol 29(8):1634–1657. https://doi.org/10.1093/annonc/mdy192

    Article  CAS  Google Scholar 

  3. Gao JJ, Cheng J, Bloomquist E, Sanchez J, Wedam SB, Singh H et al (2020) 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 21(2):250–260. https://doi.org/10.1016/S1470-2045(19)30804-6

    Article  CAS  PubMed  Google Scholar 

  4. Pandey K, An HJ, Kim SK, Lee SA, Kim S, Lim SM et al (2019) Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: a review. Int J Cancer 145(5):1179–1188. https://doi.org/10.1002/ijc.32020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Du Q, Guo X, Wang M, Li Y, Sun X, Li Q (2020) The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol 13(1):41. https://doi.org/10.1186/s13045-020-00880-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell. 144(5):646–674. https://doi.org/10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  7. Barnum KJ, O’Connell MJ (2014) Cell cycle regulation by checkpoints. Methods Mol Biol 1170:29–40. https://doi.org/10.1007/978-1-4939-0888-2_2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Planas-Silva MD, Weinberg RA (1997) The restriction point and control of cell proliferation. Curr Opin Cell Biol 9(6):768–772. https://doi.org/10.1016/s0955-0674(97)80076-2

    Article  CAS  PubMed  Google Scholar 

  9. Diehl JA (2002) Cycling to cancer with cyclin D1. Cancer Biol Ther 1(3):226–231. https://doi.org/10.4161/cbt.72

    Article  CAS  PubMed  Google Scholar 

  10. Burkhart DL, Sage J (2008) Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 8(9):671–682. https://doi.org/10.1038/nrc2399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gao X, Leone GW, Wang H (2020) Cyclin D-CDK4/6 functions in cancer. Adv Cancer Res 148:147–169. https://doi.org/10.1016/bs.acr.2020.02.002

    Article  PubMed  Google Scholar 

  12. Kollmann K, Heller G, Schneckenleithner C, Warsch W, Scheicher R, Ott RG et al (2013) A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell 24(2):167–181. https://doi.org/10.1016/j.ccr.2013.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hwang HC, Clurman BE (2005) Cyclin E in normal and neoplastic cell cycles. Oncogene 24(17):2776–2786. https://doi.org/10.1038/sj.onc.1208613

    Article  CAS  PubMed  Google Scholar 

  14. Martinez-Alonso D, Malumbres M (2020) Mammalian cell cycle cyclins. Semin Cell Dev Biol 107:28–35. https://doi.org/10.1016/j.semcdb.2020.03.009

    Article  CAS  PubMed  Google Scholar 

  15. Malumbres M, Sotillo R, Santamaria D, Galan J, Cerezo A, Ortega S et al (2004) Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118(4):493–504. https://doi.org/10.1016/j.cell.2004.08.002

    Article  CAS  PubMed  Google Scholar 

  16. Alvarez-Fernandez M, Malumbres M (2020) Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell 37(4):514–529. https://doi.org/10.1016/j.ccell.2020.03.010

    Article  CAS  PubMed  Google Scholar 

  17. Malumbres M, Barbacid M (2001) To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1(3):222–231. https://doi.org/10.1038/35106065

    Article  CAS  PubMed  Google Scholar 

  18. Cardoso F, Spence D, Mertz S, Corneliussen-James D, Sabelko K, Gralow J et al (2018) Global analysis of advanced/metastatic breast cancer: decade report (2005–2015). Breast 39:131–138. https://doi.org/10.1016/j.breast.2018.03.002

    Article  PubMed  Google Scholar 

  19. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752. https://doi.org/10.1038/35021093

    Article  CAS  PubMed  Google Scholar 

  20. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 98(19):10869–10874. https://doi.org/10.1073/pnas.191367098

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE et al (2010) RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle 9(20):4153–4163. https://doi.org/10.4161/cc.9.20.13454

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hart CD, Migliaccio I, Malorni L, Guarducci C, Biganzoli L, Di Leo A (2015) Challenges in the management of advanced, ER-positive, HER2-negative breast cancer. Nat Rev Clin Oncol 12(9):541–552. https://doi.org/10.1038/nrclinonc.2015.99

    Article  PubMed  Google Scholar 

  23. Filmus J, Robles AI, Shi W, Wong MJ, Colombo LL, Conti CJ (1994) Induction of cyclin D1 overexpression by activated ras. Oncogene 9(12):3627–3633

    CAS  PubMed  Google Scholar 

  24. Bartkova J, Lukas J, Muller H, Lutzhoft D, Strauss M, Bartek J (1994) Cyclin D1 protein expression and function in human breast cancer. Int J Cancer 57(3):353–361. https://doi.org/10.1002/ijc.2910570311

    Article  CAS  PubMed  Google Scholar 

  25. Trere D, Brighenti E, Donati G, Ceccarelli C, Santini D, Taffurelli M et al (2009) High prevalence of retinoblastoma protein loss in triple-negative breast cancers and its association with a good prognosis in patients treated with adjuvant chemotherapy. Ann Oncol Official Journal of the Eur Soci Med Oncol 20(11):1818–1823. https://doi.org/10.1093/annonc/mdp209

    Article  CAS  Google Scholar 

  26. Stefansson OA, Jonasson JG, Olafsdottir K, Hilmarsdottir H, Olafsdottir G, Esteller M et al (2011) CpG island hypermethylation of BRCA1 and loss of pRb as co-occurring events in basal/triple-negative breast cancer. Epigenetics 6(5):638–649. https://doi.org/10.4161/epi.6.5.15667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Witkiewicz AK, Knudsen ES (2014) Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res BCR 16(3):207. https://doi.org/10.1186/bcr3652

    Article  PubMed  Google Scholar 

  28. Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL (2011) Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11(8):558–572. https://doi.org/10.1038/nrc3090

    Article  CAS  PubMed  Google Scholar 

  29. Peyressatre M, Prevel C, Pellerano M, Morris MC (2015) Targeting cyclin-dependent kinases in human cancers: from small molecules to peptide inhibitors. Cancers 7(1):179–237. https://doi.org/10.3390/cancers7010179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES (2015) The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 14(2):130–146. https://doi.org/10.1038/nrd4504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO et al (2015) 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(1):25–35. https://doi.org/10.1016/S1470-2045(14)71159-3

    Article  CAS  PubMed  Google Scholar 

  32. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K et al (2016) Palbociclib and Letrozole in advanced breast Cancer. N Engl J Med 375(20):1925–1936. https://doi.org/10.1056/NEJMoa1607303

    Article  CAS  PubMed  Google Scholar 

  33. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H et al (2015) Palbociclib in hormone-receptor-positive advanced breast Cancer. N Engl J Med 373(3):209–219. https://doi.org/10.1056/NEJMoa1505270

    Article  CAS  PubMed  Google Scholar 

  34. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S et al (2016) Ribociclib as first-line therapy for HR-positive, advanced breast Cancer. N Engl J Med 375(18):1738–1748. https://doi.org/10.1056/NEJMoa1609709

    Article  CAS  PubMed  Google Scholar 

  35. Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA et al (2018) 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 36(24):2465–2472. https://doi.org/10.1200/JCO.2018.78.9909

    Article  CAS  PubMed  Google Scholar 

  36. Goetz MP, Toi M, Campone M, Sohn J, Paluch-Shimon S, Huober J et al (2017) MONARCH 3: Abemaciclib as initial therapy for advanced breast Cancer. J Clin Oncol 35(32):3638–3646. https://doi.org/10.1200/JCO.2017.75.6155

    Article  CAS  PubMed  Google Scholar 

  37. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X et al (2017) 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 35(25):2875–2884. https://doi.org/10.1200/JCO.2017.73.7585

    Article  CAS  PubMed  Google Scholar 

  38. Tripathy D, Im SA, Colleoni M, Franke F, Bardia A, Harbeck N et al (2018) Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 19(7):904–915. https://doi.org/10.1016/S1470-2045(18)30292-4

    Article  CAS  PubMed  Google Scholar 

  39. Dickler MN, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt D et al (2017) 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 Off J Am Assoc Cancer Res 23(17):5218–5224. https://doi.org/10.1158/1078-0432.CCR-17-0754

    Article  CAS  Google Scholar 

  40. Rossi L, McCartney A, Risi E, De Santo I, Migliaccio I, Malorni L et al (2019) Cyclin-dependent kinase 4/6 inhibitors in neoadjuvant endocrine therapy of hormone receptor-positive breast Cancer. Clin Breast Cancer 19(6):392–398. https://doi.org/10.1016/j.clbc.2019.05.019

    Article  CAS  PubMed  Google Scholar 

  41. Malumbres M (2019) CDK4/6 inhibitors: what is the best cocktail? Clin Cancer Res Off J Am Assoc Cancer Res 25(1):6–8. https://doi.org/10.1158/1078-0432.CCR-18-2177

    Article  CAS  Google Scholar 

  42. Kassem L, Shohdy KS, Lasheen S, Abdel-Rahman O, Bachelot T (2018) Hematological adverse effects in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors: a systematic review and meta-analysis. Breast Cancer 25(1):17–27. https://doi.org/10.1007/s12282-017-0818-4

    Article  PubMed  Google Scholar 

  43. Guarducci C, Bonechi M, Boccalini G, Benelli M, Risi E, Di Leo A et al (2017) Mechanisms of resistance to CDK4/6 inhibitors in breast Cancer and potential biomarkers of response. Breast care 12(5):304–308. https://doi.org/10.1159/000484167

    Article  PubMed  PubMed Central  Google Scholar 

  44. McCartney A, Migliaccio I, Bonechi M, Biagioni C, Romagnoli D, De Luca F et al (2019) Mechanisms of resistance to CDK4/6 inhibitors: potential implications and biomarkers for clinical practice. Front Oncol 9:666. https://doi.org/10.3389/fonc.2019.00666

    Article  PubMed  PubMed Central  Google Scholar 

  45. Johnson J, Thijssen B, McDermott U, Garnett M, Wessels LF, Bernards R (2016) Targeting the RB-E2F pathway in breast cancer. Oncogene 35(37):4829–4835. https://doi.org/10.1038/onc.2016.32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ et al (2009) 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 BCR 11(5):R77. https://doi.org/10.1186/bcr2419

    Article  CAS  PubMed  Google Scholar 

  47. Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES (2010) Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29(28):4018–4032. https://doi.org/10.1038/onc.2010.154

    Article  CAS  PubMed  Google Scholar 

  48. Malorni L, Piazza S, Ciani Y, Guarducci C, Bonechi M, Biagioni C et al (2016) A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer. Oncotarget 7(42):68012–68022. https://doi.org/10.18632/oncotarget.12010

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bollard J, Miguela V, Ruiz de Galarreta M, Venkatesh A, Bian CB, Roberto MP et al (2017) Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut. 66(7):1286–1296. https://doi.org/10.1136/gutjnl-2016-312268

    Article  CAS  PubMed  Google Scholar 

  50. Gopalan PK, Villegas AG, Cao C, Pinder-Schenck M, Chiappori A, Hou W et al (2018) CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition. Oncotarget 9(100):37352–37366. https://doi.org/10.18632/oncotarget.26424

    Article  PubMed  PubMed Central  Google Scholar 

  51. Dean JL, McClendon AK, Hickey TE, Butler LM, Tilley WD, Witkiewicz AK et al (2012) Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analyses of human tumors. Cell Cycle 11(14):2756–2761. https://doi.org/10.4161/cc.21195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE et al (2012) Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst 104(6):476–487. https://doi.org/10.1093/jnci/djs002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Herrera-Abreu MT, Palafox M, Asghar U, Rivas MA, Cutts RJ, Garcia-Murillas I et al (2016) Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast Cancer. Cancer Res 76(8):2301–2313. https://doi.org/10.1158/0008-5472.CAN-15-0728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Condorelli R, Spring L, O’Shaughnessy J, Lacroix L, Bailleux C, Scott V et al (2018) Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann Oncol Off J Eur Soc Med Oncol 29(3):640–645. https://doi.org/10.1093/annonc/mdx784

    Article  CAS  Google Scholar 

  55. Xu B, Krie A, De P, Williams C, Elsey R, Klein J et al (2017) Utilizing tumor and plasma liquid biopsy in treatment decision making for an estrogen receptor-positive advanced breast Cancer patient. Cureus 9(6):e1408. https://doi.org/10.7759/cureus.1408

    Article  PubMed  PubMed Central  Google Scholar 

  56. Li Z, Razavi P, Li Q, Toy W, Liu B, Ping C et al (2018) Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the hippo pathway. Cancer Cell 34(6):893–905 e8. https://doi.org/10.1016/j.ccell.2018.11.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wander SA, Cohen O, Gong X, Johnson GN, Buendia-Buendia JE, Lloyd MR et al (2020) 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 10(8):1174–1193. https://doi.org/10.1158/2159-8290.CD-19-1390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. DeMichele A, Clark AS, Tan KS, Heitjan DF, Gramlich K, Gallagher M et al (2015) CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res Off J Am Assoc Cancer Res 21(5):995–1001. https://doi.org/10.1158/1078-0432.CCR-14-2258

    Article  CAS  Google Scholar 

  59. O’Leary B, Cutts RJ, Liu Y, Hrebien S, Huang X, Fenwick K et al (2018) 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. https://doi.org/10.1158/2159-8290.CD-18-0264

    Article  PubMed  PubMed Central  Google Scholar 

  60. Portman N, Alexandrou S, Carson E, Wang S, Lim E, Caldon CE (2019) Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer. Endocr Relat Cancer 26(1):R15–R30. https://doi.org/10.1530/ERC-18-0317

    Article  CAS  PubMed  Google Scholar 

  61. Chicas A, Wang X, Zhang C, McCurrach M, Zhao Z, Mert O et al (2010) Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell 17(4):376–387. https://doi.org/10.1016/j.ccr.2010.01.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Asghar US, Barr AR, Cutts R, Beaney M, Babina I, Sampath D et al (2017) Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast Cancer. Clin Cancer Res Off J Am Assoc Cancer Res 23(18):5561–5572. https://doi.org/10.1158/1078-0432.CCR-17-0369

    Article  CAS  Google Scholar 

  63. Caldon CE, Sergio CM, Kang J, Muthukaruppan A, Boersma MN, Stone A et al (2012) Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther 11(7):1488–1499. https://doi.org/10.1158/1535-7163.MCT-11-0963

    Article  CAS  PubMed  Google Scholar 

  64. Gong X, Litchfield LM, Webster Y, Chio LC, Wong SS, Stewart TR et al (2017) Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor Abemaciclib. Cancer Cell 32(6):761–776 e6. https://doi.org/10.1016/j.ccell.2017.11.006

    Article  CAS  PubMed  Google Scholar 

  65. Turner NC, Liu Y, Zhu Z, Loi S, Colleoni M, Loibl S et al (2019) Cyclin E1 expression and Palbociclib efficacy in previously treated hormone receptor-positive metastatic breast Cancer. J Clin Oncol 37(14):1169–1178. https://doi.org/10.1200/JCO.18.00925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ma CX, Gao F, Luo J, Northfelt DW, Goetz M, Forero A et al (2017) 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 Off J Am Assoc Cancer Res 23(15):4055–4065. https://doi.org/10.1158/1078-0432.CCR-16-3206

    Article  CAS  Google Scholar 

  67. Guarducci C, Bonechi M, Benelli M, Biagioni C, Boccalini G, Romagnoli D et al (2018) Cyclin E1 and Rb modulation as common events at time of resistance to palbociclib in hormone receptor-positive breast cancer. NPJ Breast Cancer 4:38. https://doi.org/10.1038/s41523-018-0092-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Yang C, Li Z, Bhatt T, Dickler M, Giri D, Scaltriti M et al (2017) Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 36(16):2255–2264. https://doi.org/10.1038/onc.2016.379

    Article  CAS  PubMed  Google Scholar 

  69. Iida M, Nakamura M, Tokuda E, Toyosawa D, Niwa T, Ohuchi N et al (2019) The p21 levels have the potential to be a monitoring marker for ribociclib in breast cancer. Oncotarget 10(47):4907–4918. https://doi.org/10.18632/oncotarget.27127

    Article  PubMed  PubMed Central  Google Scholar 

  70. Jansen VM, Bhola NE, Bauer JA, Formisano L, Lee KM, Hutchinson KE et al (2017) Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast Cancer. Cancer Res 77(9):2488–2499. https://doi.org/10.1158/0008-5472.CAN-16-2653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Song X, Liu X, Wang H, Wang J, Qiao Y, Cigliano A et al (2019) Combined CDK4/6 and pan-mTOR inhibition is synergistic against intrahepatic cholangiocarcinoma. Clin Cancer Res Off J Am Assoc Cancer Res 25(1):403–413. https://doi.org/10.1158/1078-0432.CCR-18-0284

    Article  CAS  Google Scholar 

  72. Patel P, Asbach B, Shteyn E, Gomez C, Coltoff A, Bhuyan S et al (2015) Brk/protein tyrosine kinase 6 phosphorylates p27KIP1, regulating the activity of cyclin D-cyclin-dependent kinase 4. Mol Cell Biol 35(9):1506–1522. https://doi.org/10.1128/MCB.01206-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Fisher RP (2005) Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 118(Pt 22):5171–5180. https://doi.org/10.1242/jcs.02718

    Article  CAS  PubMed  Google Scholar 

  74. Pancholi S, Ribas R, Simigdala N, Schuster E, Nikitorowicz-Buniak J, Ressa A et al (2020) Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities. Oncogene. https://doi.org/10.1038/s41388-020-1284-6

  75. Attia YM, Shouman SA, Salama SA, Ivan C, Elsayed AM, Amero P et al (2020) Blockade of CDK7 reverses endocrine therapy resistance in breast cancer. Int J Mol Sci 21(8). https://doi.org/10.3390/ijms21082974

  76. Opyrchal M, Salisbury JL, Zhang S, McCubrey J, Hawse J, Goetz MP et al (2014) Aurora-a mitotic kinase induces endocrine resistance through down-regulation of ERalpha expression in initially ERalpha+ breast cancer cells. PLoS One 9(5):e96995. https://doi.org/10.1371/journal.pone.0096995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Takeshita T, Yamamoto Y, Yamamoto-Ibusuki M, Tomiguchi M, Sueta A, Murakami K et al (2018) Clinical significance of plasma cell-free DNA mutations in PIK3CA, AKT1, and ESR1 gene according to treatment lines in ER-positive breast cancer. Mol Cancer 17(1):67. https://doi.org/10.1186/s12943-018-0808-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Costa C, Wang Y, Ly A, Hosono Y, Murchie E, Walmsley CS et al (2020) PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kalpha inhibitors in breast Cancer. Cancer Discov 10(1):72–85. https://doi.org/10.1158/2159-8290.CD-18-0830

    Article  CAS  PubMed  Google Scholar 

  79. Andre F, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS et al (2019) Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast Cancer. N Engl J Med 380(20):1929–1940. https://doi.org/10.1056/NEJMoa1813904

    Article  CAS  PubMed  Google Scholar 

  80. Formisano L, Lu Y, Servetto A, Hanker AB, Jansen VM, Bauer JA et al (2019) Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun 10(1):1373. https://doi.org/10.1038/s41467-019-09068-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Cornell L, Wander SA, Visal T, Wagle N, Shapiro GI (2019) MicroRNA-mediated suppression of the TGF-beta pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep 26(10):2667–2680 e7. https://doi.org/10.1016/j.celrep.2019.02.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. de Leeuw R, McNair C, Schiewer MJ, Neupane NP, Brand LJ, Augello MA et al (2018) MAPK reliance via acquired CDK4/6 inhibitor resistance in Cancer. Clin Cancer Res Off J Am Assoc Cancer Res 24(17):4201–4214. https://doi.org/10.1158/1078-0432.CCR-18-0410

    Article  Google Scholar 

  83. Jeselsohn R, Yelensky R, Buchwalter G, Frampton G, Meric-Bernstam F, Gonzalez-Angulo AM et al (2014) Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res 20(7):1757–1767. https://doi.org/10.1158/1078-0432.CCR-13-2332

    Article  CAS  Google Scholar 

  84. Robinson DR, Wu YM, Vats P, Su F, Lonigro RJ, Cao X et al (2013) Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet 45(12):1446–1451. https://doi.org/10.1038/ng.2823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Nayar U, Cohen O, Kapstad C, Cuoco MS, Waks AG, Wander SA et al (2019) Acquired HER2 mutations in ER(+) metastatic breast cancer confer resistance to estrogen receptor-directed therapies. Nat Genet 51(2):207–216. https://doi.org/10.1038/s41588-018-0287-5

    Article  CAS  PubMed  Google Scholar 

  86. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M et al (2013) ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet 45(12):1439–1445. https://doi.org/10.1038/ng.2822

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R (2015) ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol 12(10):573–583. https://doi.org/10.1038/nrclinonc.2015.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Iida M, Toyosawa D, Nakamura M, Tsuboi K, Tokuda E, Niwa T et al (2020) Decreased ER dependency after acquired resistance to CDK4/6 inhibitors. Breast Cancer. https://doi.org/10.1007/s12282-020-01090-3

  89. Raspe E, Coulonval K, Pita JM, Paternot S, Rothe F, Twyffels L et al (2017) CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib. EMBO Mol Med 9(8):1052–1066. https://doi.org/10.15252/emmm.201607084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Michaloglou C, Crafter C, Siersbaek R, Delpuech O, Curwen JO, Carnevalli LS et al (2018) 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 17(5):908–920. https://doi.org/10.1158/1535-7163.MCT-17-0537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Occhipinti G, Romagnoli E, Santoni M, Cimadamore A, Sorgentoni G, Cecati M et al (2020) Sequential or concomitant inhibition of cyclin-dependent kinase 4/6 before mTOR pathway in hormone-positive HER2 negative breast Cancer: biological insights and clinical implications. Front Genet 11:349. https://doi.org/10.3389/fgene.2020.00349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Whittle JR, Vaillant F, Surgenor E, Policheni AN, Giner G, Capaldo BD et al (2020) Dual targeting of CDK4/6 and BCL2 pathways augments tumor response in estrogen receptor-positive breast Cancer. Clin Cancer Res Off J Am Assoc Cancer Res 26(15):4120–4134. https://doi.org/10.1158/1078-0432.CCR-19-1872

    Article  CAS  Google Scholar 

  93. Lok SW, Whittle JR, Vaillant F, Teh CE, Lo LL, Policheni AN et al (2019) A phase Ib dose-escalation and expansion study of the BCL2 inhibitor Venetoclax combined with tamoxifen in ER and BCL2-positive metastatic breast Cancer. Cancer Discov 9(3):354–369. https://doi.org/10.1158/2159-8290.CD-18-1151

    Article  CAS  PubMed  Google Scholar 

  94. Patel HK, Tao N, Lee KM, Huerta M, Arlt H, Mullarkey T et al (2019) Elacestrant (RAD1901) exhibits anti-tumor activity in multiple ER+ breast cancer models resistant to CDK4/6 inhibitors. Breast Cancer Res BCR 21(1):146. https://doi.org/10.1186/s13058-019-1230-0

    Article  CAS  PubMed  Google Scholar 

  95. Bardia A, Aftimos P, Bihani T, Anderson-Villaluz AT, Jung J, Conlan MG et al (2019) EMERALD: phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Future Oncol 15(28):3209–3218. https://doi.org/10.2217/fon-2019-0370

    Article  CAS  PubMed  Google Scholar 

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  1. Oncology Unit, 3rd Department of Medicine, ‘Sotiria’ General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Georgia Gomatou, Ioannis Trontzas, Stephanie Ioannou, Maria Drizou, Nikolaos Syrigos & Elias Kotteas

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  1. Georgia Gomatou
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  2. Ioannis Trontzas
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  3. Stephanie Ioannou
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GG: Conceptualization, Literature review, Data analysis, Writing – original draft, IT, SI, MD, and NS: Literature review, Data analysis, Writing – review and editing, EK: Writing – editing and critical revision, Supervision.

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Gomatou, G., Trontzas, I., Ioannou, S. et al. Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors. Mol Biol Rep 48, 915–925 (2021). https://doi.org/10.1007/s11033-020-06100-3

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