Top

Published in:

01-06-2022 | SCLC | Neuroendocrine Neoplasms (NS Reed, Section Editor)

Cyclin-dependent Kinases 4/6 Inhibitors in Neuroendocrine Neoplasms: from Bench to Bedside

Authors: Maria João de Sousa, Lorenzo Gervaso, Monica Isabel Meneses-Medina, Francesca Spada, Omar Abdel-Rahman, Nicola Fazio

Published in: Current Oncology Reports | Issue 6/2022

Abstract

Purpose of review

Cyclin-dependent kinases (CDKs) are key regulators that play an important role in cell division. Palbociclib, ribociclib and abemaciclib showed significant antitumor activity in several malignancies and, recently, also a myeloprotective effect for trilaciclib when added to chemotherapy. The purpose of this review is to highlight the current evidence for CDK4/6 inhibitors in neuroendocrine neoplasms (NENs).

Recent findings

Preclinical results showed a promising antitumor activity of CDK4/6 inhibitors in neuroendocrine tumors (NETs), but so far, the very few small clinical trials did not show a strong impact on progression free survival (PFS) and objective response in NETs. Meanwhile, the CDK4/6 inhibitor trilaciclib revealed significant effects in reducing chemotherapy-induced myelosuppression in small cell lung cancer (SCLC).

Summary

Up to date, CDK4/6 inhibitors are still considered investigational in NETs as antitumor agents, whereas trilaciclib can be used in the routine clinical practice in extensive stage SCLC patients for reducing myelotoxicity of standard chemotherapy.

Dinter H, Bohnenberger H, Beck J, Bornemann-Kolatzki K, Schütz E, Küffer S, et al. Molecular classification of neuroendocrine tumors of the thymus. J Thorac Oncol. 2019;14(8):1472–83. https://doi.org/10.1016/j.jtho.2019.04.015.CrossRefPubMed

• Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. In: Histopathology. Blackwell Publishing Ltd. 2020;76:182–188. https://doi.org/10.1111/his.13975. New 2019 WHO classification of GEP-NENs.

• Thoracic Tumours, WHO classification of tumours. 2021. Available at: https://tumourclassification.iarc.who.int/welcome/. Accessed 21 Oct 2021. WHO classification of the thoracic NENs.

Tang LH, Contractor T, Clausen R, Klimstra DS, Du YCN, Allen PJ, et al. Attenuation of the retinoblastoma pathway in pancreatic neuroendocrine tumors due to increased Cdk4/Cdk6. Clin Cancer Res. 2012;18(17):4612–20. https://doi.org/10.1158/1078-0432.CCR-11-3264.CrossRefPubMed

Shi Y, Qian ZR, Zhang S, Li W, Masugi Y, Li T, et al. Cell cycle protein expression in neuroendocrine tumors: association of CDK4/CDK6, CCND1, and phosphorylated retinoblastoma protein with proliferative index. Pancreas. 2017;46(10):1347–53. https://doi.org/10.1097/MPA.0000000000000944.CrossRefPubMedPubMedCentral

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

Obaya AJ, Sedivy JM. Review Regulation of cyclin-Cdk activity in mammalian cells. CMLS, Cell Mol Life Sci 2002;59. https://doi.org/10.1007/s00018-002-8410-1.

Prada ETA, Nölting S, Spoettl G, Maurer J, Auernhammer CJ. The novel cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) alone and in dual-targeting approaches demonstrates antitumoral efficacy in neuroendocrine tumors in vitro. Neuroendocrinology. 2017;106(1):58–73. https://doi.org/10.1159/000463386.CrossRef

Goel S, DeCristo MJ, McAllister SS, Zhao JJ. CDK4/6 Inhibition in cancer: beyond cell cycle arrest. Trends Cell Biol. Elsevier Ltd. 2018;28:911–25. https://doi.org/10.1016/j.tcb.2018.07.002.

10.

Du Q, Guo X, Wang M, Li Y, Sun X, Li Q. The application and prospect of CDK4/6 inhibitors in malignant solid tumors. J Hematol Oncol. BioMed Central Ltd. 2020;13:1–12. https://doi.org/10.1186/s13045-020-00880-8.

11.

Poratti M, Marzaro G. Third-generation CDK inhibitors: A review on the synthesis and binding modes of palbociclib, ribociclib and abemaciclib. Eur J Med Chem. Elsevier Masson s.r.l. 2019;172: 143–53. https://doi.org/10.1016/j.ejmech.2019.03.064.

12.

Klein ME, Kovatcheva M, Davis LE, Tap WD, Koff A. CDK4/6 Inhibitors: The mechanism of action may not be as simple as once thought. Cancer Cell. Cell Press. 2018;34:9–20. https://doi.org/10.1016/j.ccell.2018.03.023.

13.

George MA, Qureshi S, Omene C, Toppmeyer DL, Ganesan S. Clinical and pharmacologic differences of CDK4/6 inhibitors in breast cancer. Front Oncol. Frontiers Media S.A. 2021;11:2471. https://doi.org/10.3389/fonc.2021.693104.

14.

Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? NPJ Breast Cancer. 2019;5(1). https://doi.org/10.1038/s41523-019-0121-y

15.

Gervaso L, Montero AJ, Jia X, Khorana AA. Venous thromboembolism in breast cancer patients receiving cyclin-dependent kinase inhibitors. J Thromb Haemost. 2020;18(1):162–8. https://doi.org/10.1111/jth.14630.CrossRefPubMed

16.

US FDA. Palbociclib (IBRANCE). 2017. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/palbociclib-ibrance. Accessed 23 Oct 2021.

17.

US FDA. FDA approves abemaciclib as initial therapy for HR-positive, HER2-negative metastatic breast cancer. 2018. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abemaciclib-initial-therapy-hr-positive-her2-negative-metastatic-breast-cancer. Accessed 23 Oct 2021.

18.

US FDA. FDA expands ribociclib indication in HR-positive, HER2-negative advanced or metastatic breast cancer. 2018. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-expands-ribociclib-indication-hr-positive-her2-negative-advanced-or-metastatic-breast-cancer. Accessed 23 Oct 2021.

19.

Powell K, Prasad V. Concerning FDA approval of trilaciclib (Cosela) in extensive-stage small-cell lung cancer. Transl Oncol. 2021;14(11). https://doi.org/10.1016/j.tranon.2021.101206.

20.

Dhillon S. Trilaciclib: First Approval. Drugs. 2021;81(7):867–74. https://doi.org/10.1007/s40265-021-01508-y.CrossRefPubMed

21.

US FDA. FDA approves drug to reduce bone marrow suppression caused by chemotherapy. 2021. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-drug-reduce-bone-marrow-suppression-caused-chemotherapy. Accessed 1 Nov 2021.

22.

Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36(2):173–84. https://doi.org/10.1097/PAS.0b013e3182417d36.CrossRefPubMedPubMedCentral

23.

Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE. Pancreatic neuroendocrine tumors: molecular mechanisms and therapeutic targets. Cancers. 2021;13(20):5117. https://doi.org/10.3390/cancers13205117.CrossRefPubMedPubMedCentral

24.

•• Grande E, Teulé A, Alonso‐Gordoa T, Jiménez‐Fonseca P, Benavent M, Capdevila J, et al. The PALBONET Trial: a phase II Study of palbociclib in metastatic grade 1 and 2 pancreatic neuroendocrine tumors (GETNE‐1407). The Oncologist. 2020;25(9):745. https://doi.org/10.1634/theoncologist.2020-0033. A phase II trial to assess the activity and safety of palbociclib as single agent in metastatic grade 1/2 panNETs. No objective responses were observed with palbociclib in this study.

25.

•• Dasari A, Halperin D, Coya T, Mahvash A, Zorilla I, Meric-Bernstam F, et al. A pilot study of the cyclin dependent kinases 4, 6 Inhibitor ribociclib in patients with foregut neuroendocrine tumors. In: NANETS 2018 Symposium Abstracts. 2018. A phase II trial to study ribociclib in the treatment of patients with NETs of the foregut. Although there were no objective responses, an improvement in PFS was noted.

26.

Dasari A, Halperin D, Coya T, Mahvash A, Zorilla I, Meric-Bernstam F, et al. A pilot study of the cyclin dependent kinases 4, 6 inhibitor ribociclib in patients with foregut neuroendocrine tumors. In: ENETS 2018 Conference Abstracts. 2018.

27.

Pavel ME, Singh S, Strosberg JR, Bubuteishvili-Pacaud L, Degtyarev E, Neary MP, et al. Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(10):1411–22. https://doi.org/10.1016/S1470-2045(17)30471-0.CrossRefPubMed

28.

Yao JC, Pavel M, Lombard-Bohas C, van Cutsem E, Voi M, Brandt U, et al. Everolimus for the treatment of advanced pancreatic neuroendocrine tumors: Overall survival and circulating biomarkers from the randomized, Phase III RADIANT-3 study. J Clin Oncol. 2016;34(32):3906–13. https://doi.org/10.1200/JCO.2016.68.0702.CrossRefPubMedPubMedCentral

29.

Jin XF, Spöttl G, Maurer J, Nölting S, Auernhammer CJ. Antitumoral activity of the mek inhibitor trametinib (Tmt212) alone and in combination with the cdk4/6 inhibitor ribociclib (lee011) in neuroendocrine tumor cells in vitro. Cancers. 2021;13(6). https://doi.org/10.3390/cancers13061485.

30.

•• Raj N, Zheng Y, Hauser H, Chou J, Rafailov J, Bou-Ayache J, et al. Ribociclib and everolimus in well-differentiated foregut neuroendocrine tumors. Endocrine-Related Cancer. 2021;28(4):237–46. https://doi.org/10.1530/ERC-20-0446. A Phase II trial of ribociclib plus everolimus in the treatment of advanced NETs of the foregut. The combination was associated with toxicity and offered modest activity.

31.

Bardia A, Modi S, Oliveira M, Cortes J, Campone M, Ma B, et al. Phase Ib dose-escalation/expansion trial of ribociclib in combination with everolimus and exemestane in postmenopausal women with HR+, HER2- advanced breast cancer. Clin Cancer Res. 2020;26(24):6417–28. https://doi.org/10.1158/1078-0432.CCR-20-1068.CrossRefPubMedPubMedCentral

32.

He S, Roberts PJ, Sorrentino JA, Bisi JE, Storrie-White H, Tiessen RG, et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med. 2017;9(387). https://doi.org/10.1126/scitranslmed.aal3986.

33.

Bisi JE, Sorrentino JA, Roberts PJ, Tavares FX, Strum JC. Preclinical characterization of G1T28: A novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol Cancer Ther. 2016;15(5):783–93. https://doi.org/10.1158/1535-7163.MCT-15-0775.CrossRefPubMed

34.

Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8(2):216–33. https://doi.org/10.1158/1535-7163.MCT-15-0775.CrossRefPubMed

35.

•• Weiss JM, Csoszi T, Maglakelidze M, Hoyer RJ, Beck JT, Domine Gomez 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):1613–21. https://doi.org/10.1093/annonc/mdz278. A phase Ib and phase II trial, in which trilaciclib demonstrated an improvement in SCLC patient’s tolerability of etoposide/carboplatin by myelopreservation across multiple hematopoietic lineages.

36.

•• Hart LL, Ferrarotto R, Andric ZG, Beck JT, Subramanian J, Radosavljevic J, et al. Myelopreservation with trilaciclib in patients receiving topotecan for small cell lung cancer: results from a randomized, double-blind, placebo-controlled phase ii study. Adv Ther. 2021;38.1: 350–365. https://doi.org/10.1007/s12325-020-01538-0. A phase II trial of trilaciclib prior to topotecan for the treatment of previously treated SCLC demonstrated a reduction in chemotherapy-induced myelosuppression, improved safety profile, improved quality of life and no detrimental effects on antitumor efficacy.

37.

•• Daniel D, Kuchava V, Bondarenko I, Ivashchuk O, Reddy S, Jaal J, et al. Trilaciclib prior to chemotherapy and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer: A multicentre, randomised, double-blind, placebo-controlled Phase II trial. Int J Cancer. 2021;148(10):2557–70. https://doi.org/10.1002/ijc.33453. A Phase II study confirmed the myelopreservation benefits of trilaciclib administered prior to carboplatin, etoposide and atezolizumab for SCLC.

38.

Weiss J, Goldschmidt J, Andric Z, Dragnev KH, Gwaltney C, Skaltsa K, et al. Effects of trilaciclib on chemotherapy-induced myelosuppression and patient-reported outcomes in patients with extensive-stage small cell lung cancer: pooled results from three phase ii randomized, double-blind, placebo-controlled studies. Clin Lung Cancer. 2021;22(5):449–60. https://doi.org/10.1016/j.cllc.2021.03.010.CrossRefPubMed

39.

Portman N, Alexandrou S, Carson E, Wang S, Lim E, Caldon CE. Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer. In: Endocrine-related cancer. BioScientifica Ltd. 2019;26:R15–30. https://doi.org/10.1530/ERC-18-0317.

40.

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

41.

Pandey K, An HJ, Kim SK, Lee SA, Kim S, Lim SM, et al. Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review. Int J Cancer. Wiley-Liss Inc. 2019;145:1179–88. https://doi.org/10.1002/ijc.32020.

42.

Huang W, Wang H. Potential biomarkers of resistance to CDK4/6 inhibitors: a narrative review of preclinical and clinical studies. Transl Breast Cancer Res. 2021;2:12–12. https://doi.org/10.21037/tbcr-20-52.CrossRef

43.

Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. Cell Press. 2017;3: 39–55. https://doi.org/10.1016/j.trecan.2016.11.006.

44.

Sobhani N, D’Angelo A, Pittacolo M, Roviello G, Miccoli A, Corona SP, et al. Updates on the CDK4/6 inhibitory strategy and combinations in breast cancer. Cells. 2019;8(4):321. https://doi.org/10.3390/cells8040321.CrossRefPubMedCentral

45.

Takahashi D, Kojima M, Suzuki T, Sugimoto M, Kobayashi S, Takahashi S, et al. Profiling the tumour immune microenvironment in pancreatic neuroendocrine neoplasms with multispectral imaging indicates distinct subpopulation characteristics concordant with WHO 2017 classification. Sci Rep. 2018;8(1). https://doi.org/10.1038/s41598-018-31383-9.

46.

Takkenkamp TJ, Jalving M, Hoogwater FJH, Walenkamp AME. The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors. Endocrine-related Cancer. BioScientifica Ltd. 2020;27: R329–43. https://doi.org/10.1530/ERC-20-0113.

47.

Goel S, Decristo MJ, Watt AC, Brinjones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–5. https://doi.org/10.1038/nature23465.CrossRefPubMedPubMedCentral

48.

Álvarez-Fernández M, Malumbres M. Mechanisms of sensitivity and resistance to CDK4/6 inhibition. In: Cancer Cell. Cell Press. 2020;37:514–29. https://doi.org/10.1016/j.ccell.2020.03.010.

49.

Small J, Washburn E, Millington K, Zhu J, Holder SL. The addition of abemaciclib to sunitinib induces regression of renal cell carcinoma xenograft tumors. 2017;8(56):95116–95134.https://doi.org/10.18632/oncotarget.19618.

50.

O’Shaughnessy J, Wright GS, Thummala A, Danso M, Popovic LS, Pluard T, et al. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial. In: 2020 San Antonio Breast Cancer Symposium. 2020.

Title: Cyclin-dependent Kinases 4/6 Inhibitors in Neuroendocrine Neoplasms: from Bench to Bedside
Authors: Maria João de Sousa
Lorenzo Gervaso
Monica Isabel Meneses-Medina
Francesca Spada
Omar Abdel-Rahman
Nicola Fazio
Publication date: 01-06-2022
Publisher: Springer US
Keywords: SCLC
SCLC
Neuroendocrine Tumor
Cytostatic Therapy
Published in: Current Oncology Reports / Issue 6/2022
Print ISSN: 1523-3790
Electronic ISSN: 1534-6269
DOI: https://doi.org/10.1007/s11912-022-01251-x

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of review

Recent findings

Summary

Please log in to get access to this content

Other articles of this Issue 6/2022

Rehabilitation Needs for Patients Undergoing CAR T-Cell Therapy

Global Longitudinal Strain Monitoring to Guide Cardioprotective Medications During Anthracycline Treatment

Neutropenia and Infection Prophylaxis in Childhood Cancer

Microwave Ablation, Radiofrequency Ablation, Irreversible Electroporation, and Stereotactic Ablative Body Radiotherapy for Intermediate Size (3–5 cm) Unresectable Colorectal Liver Metastases: a Systematic Review and Meta-analysis

Approaches to First-Line Therapy for Metastatic Clear Cell Renal Cell Carcinoma

Assessment of Cancer-Associated Cachexia — How to Approach Physical Function Evaluation

Keynote webinar | Spotlight on antibody–drug conjugates in cancer