CONCLUSION

The benefits of CDK4/6i’s in PCa can be optimized by fully understanding pathways that are involved with the cell cycle, resistance patterns of CDK4/6i’s and by utilizing therapies that target driver mutations in mCRPC. Additional research is needed in these key areas in order to provide more insightful reasoning to combinatorial therapies with CDK4/6i’s to maximize efficacy and durability of response. The best opportunity for synergistic success occurs when agents are combined based on interrelated mechanisms, resistance profiles, and genomics, however, it is extremely important to consider the adverse effects of the combined agents. Precision medicine should not only aid with improving effectiveness of treatment, but also protect and identify patients who would not benefit from therapy thus avoiding toxicity and decreasing morbidity. Novel strategic combinatorial therapies for mCRPC, with a CDK4/6i as the common backbone, have the potential to improve overall survival and quality of life in a patient population with few therapeutic options.

Acknowledgments

Julie Nielsen, Mayo Clinic senior production designer.


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Disclosure

The authors report no conflicts of interest in this work.


Adam M Kase,1 John A Copland III,2 Winston Tan1

1Mayo Clinic Florida Division of Hematology Oncology, Jacksonville, FL 32224, USA; 2Mayo Clinic Florida Department of Cancer Biology, Jacksonville, FL 32224, USA

Correspondence: Adam M Kase Tel +1 904-953-0315
Fax +1 905-953-2315
Email [email protected]


References

1. Key Statistics for Prostate Cancer. American Cancer Society. Accessed April 24, 2019., 2019, https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html.

2. Overview of the treatment of castration-resistant prostate cancer (CRPC). UpToDate, 2018. (Accessed April 24, 2019., 2019 https://www.uptodate.com/contents/overview-of-the-treatment-of-castration-resistant-prostate-cancer-crpc?search=therapies%20for%20castrate%20resistant%20prostate%20cancer&source=search_result&selectedTitle=1~49&usage_type=default&display_rank=1.

3. Karp G. Cell and Molecular Biology: Concepts and Experiments. 6th ed. Hoboken, NJ: John Wiley and Sons; 2010.

4. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770–1783. doi:10.1200/JCO.2005.03.7689

5. Balk SP, Knudsen KE. AR, the cell cycle, and prostate cancer. Nucl Recept Signal. 2008;6(1):e001. doi:10.1621/nrs.06001

6. Knudsen ES, Witkiewicz AK. The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer. 2017;3(1):39–55. doi:10.1016/j.trecan.2016.11.006

7. Michael Lieberman ADM. Marks’ Basic Medical Biochemistry: A Clinical Approach. 4th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2013.

8. Topacio BR, Zatulovskiy E, Cristea S, et al. Cyclin D-Cdk4,6 drives cell-cycle progression via the retinoblastoma protein’s C-Terminal Helix. Mol Cell. 2019;74(4):758–70.e4. doi:10.1016/j.molcel.2019.03.020

9. First CDK. 4/6 inhibitor heads to market. Cancer Discov. 2015;5:339–340.

10. Finn RS, Crown JP, Ettl J, et al. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res. 2016;18(1):67. doi:10.1186/s13058-016-0721-5

11. Finn RS, Martin M, Rugo HS, et al. Palbociclib and Letrozole in advanced breast cancer. N Eng J Med. 2016;375(20):1925–1936. doi:10.1056/NEJMoa1607303

12. 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. doi:10.1056/NEJMoa1609709

13. Tan MH, Li J, Xu HE, Melcher K, Yong EL. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin. 2015;36:3–23.

14. Leung JK, Sadar MD. Non-genomic actions of the androgen receptor in prostate cancer. Front Endocrinol (Lausanne). 2017;8.

15. Peterziel H, Mink S, Schonert A, Becker M, Klocker H, Cato AC. Rapid signalling by androgen receptor in prostate cancer cells. Oncogene. 1999;18(46):6322–6329. doi:10.1038/sj.onc.1203032

16. Migliaccio A, Castoria G, Auricchio F. Analysis of androgen receptor rapid actions in cellular signaling pathways: receptor/Src association. Methods Mol Biol. 2011;776:361–370.

17. Migliaccio A, Castoria G, Di Domenico M, et al. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. EMBO J. 2000;19(20):5406–5417. doi:10.1093/emboj/19.20.5406

18. Asim M, Siddiqui IA, Hafeez BB, Baniahmad A, Mukhtar H. Src kinase potentiates androgen receptor transactivation function and invasion of androgen-independent prostate cancer C4-2 cells. Oncogene. 2008;27(25):3596–3604. doi:10.1038/sj.onc.1211016

19. Varkaris A, Katsiampoura AD, Araujo JC, Gallick GE, Corn PG. Src signaling pathways in prostate cancer. Cancer Metastasis Rev. 2014;33(2–3):595–606. doi:10.1007/s10555-013-9481-1

20. Liu X, Du L, Feng R. c-Src regulates cell cycle proteins expression through protein kinase B/glycogen synthase kinase 3 beta and extracellular signal-regulated kinases 1/2 pathways in MCF-7 cells. Acta Biochim Biophys Sin (Shanghai). 2013;45(7):586–592. doi:10.1093/abbs/gmt042

21. Liao RS, Ma S, Miao L, et al. Androgen receptor-mediated non-genomic regulation of prostate cancer cell proliferation. Future Oncol. 2013;2:187–196.

22. Sun M, Yang L, Feldman RI, et al. Activation of phosphatidylinositol 3-kinase/Akt pathway by androgen through interaction of p85alpha, androgen receptor, and Src. J Biol Chem. 2003;278(44):42992–43000. doi:10.1074/jbc.M306295200

23. Huang H, Tindall DJ. FOXO factors: a matter of life and death. Future Oncol. 2006;2(1):83–89. doi:10.2217/14796694.2.1.83

24. Di Donato M, Giovannelli P, Cernera G, et al. Non-genomic androgen action regulates proliferative/migratory signaling in stromal cells. Front Endocrinol (Lausanne). 2015;5:225. doi:10.3389/fendo.2014.00225

25. Castoria G, Giovannelli P, Di Donato M, et al. Role of non-genomic androgen signalling in suppressing proliferation of fibroblasts and fibrosarcoma cells. Cell Death Dis. 2014;5(12):e1548–e. doi:10.1038/cddis.2014.497

26. Xu Y, Chen SY, Ross KN, Balk SP. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res. 2006;66(15):7783–7792. doi:10.1158/0008-5472.CAN-05-4472

27. Fang Z, Zhang T, Dizeyi N, et al. Androgen receptor enhances p27 degradation in prostate cancer cells through rapid and selective TORC2 activation. J Biol Chem. 2012;287(3):2090–2098. doi:10.1074/jbc.M111.323303

28. Tilki D, Schaeffer EM, Evans CP. Understanding mechanisms of resistance in metastatic castration-resistant prostate cancer: the role of the androgen receptor. Eur Urol Focus. 2016;2(5):499–505. doi:10.1016/j.euf.2016.11.013

29. Comstock CES, Augello MA, Goodwin JF, et al. Targeting cell cycle and hormone receptor pathways in cancer. Oncogene. 2013;32(48):5481–5491. doi:10.1038/onc.2013.83

30. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–1228. doi:10.1016/j.cell.2015.05.001

31. Frank S, Nelson P, Vasioukhin V. Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects. F1000 Res. 2018;7.

32. Sonpavde G, Agarwal N, Pond GR, et al. Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer. Cancer. 2019;125(9):1459–1469. doi:10.1002/cncr.31959

33. Palmbos PL, Tomlins SA, Agarwal N, et al. Cotargeting AR signaling and cell cycle: a randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-positive metastatic hormone sensitive prostate cancer (mHSPC). J Clin Oncol. 2018;36(6_suppl):251. doi:10.1200/JCO.2018.36.6_suppl.251

34. McCartney A, Migliaccio I, Bonechi M, et al. Mechanisms of resistance to CDK4/6 inhibitors: potential implications and biomarkers for clinical practice. Front Oncol. 2019;9:666. doi:10.3389/fonc.2019.00666

35. 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. doi:10.1158/1078-0432.CCR-18-0410

36. 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. 2018;34(1):9–20. doi:10.1016/j.ccell.2018.03.023

37. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–1512. doi:10.1056/NEJMoa040720

38. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther. 2011;5:117–124.

39. Pienta KJ. Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol. 2001;28:3–7. doi:10.1016/S0093-7754(01)90148-4

40. Dean JL, McClendon AK, Knudsen ES. Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem. 2012;287(34):29075–29087. doi:10.1074/jbc.M112.365494

41. Clark AS, McAndrew NP, Troxel A, et al. Combination Paclitaxel and Palbociclib: results of a Phase I trial in advanced breast cancer. Clin Cancer Res. 2019;25(7):2072–2079. doi:10.1158/1078-0432.CCR-18-0790

42. Lewis C, Smith DC, Carneiro BA, et al. c15-149: A phase 1b study of the oral CDK4/6 inhibitor ribociclib in combination with docetaxel plus prednisone in metastatic castration resistant prostate cancer (mCRPC) – a prostate cancer clinical trials consortium study. J Clin Oncol. 2018;36(15_suppl):e17028–e. doi:10.1200/JCO.2018.36.15_suppl.e17028

43. Slovin SF. Sipuleucel-T: when and for whom to recommend it. Oncology. 2017;31:900–901.

44. Boettcher AN, Usman A, Morgans A, VanderWeele DJ, Sosman J, Wu JD. Past, current, and future of immunotherapies for prostate cancer. Front Oncol. 2019;9:9. doi:10.3389/fonc.2019.00009

45. Deng J, Wang ES, Jenkins RW, et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 2018;8:216–233.

46. Zhang J, Bu X, Wang H, et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature. 2018;553:91–95.

47. Shi Q, Zhu Y, Ma J, et al. Prostate cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly. Mol Cancer. 2019;18(1):170. doi:10.1186/s12943-019-1096-x

48. Abeshouse A, Ahn J, Akbani R, et al. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–1025. doi:10.1016/j.cell.2015.10.025

49. Teo ZL, Versaci S, Dushyanthen S, et al. Combined CDK4/6 and PI3Kα inhibition is synergistic and immunogenic in triple-negative breast cancer. Cancer Res. 2017;77(22):6340–6352. doi:10.1158/0008-5472.CAN-17-2210

50. Tolaney SM, Kabos P, Dickler MN, et al. Updated efficacy, safety, & PD-L1 status of patients with HR+, HER2- metastatic breast cancer administered abemaciclib plus pembrolizumab. J Clin Oncol. 2018;36(15_suppl):1059. doi:10.1200/JCO.2018.36.15_suppl.1059

51. Plummer R. Perspective on the pipeline of drugs being developed with modulation of DNA damage as a target. Clin Cancer Res. 2010;16(18):4527–4531. doi:10.1158/1078-0432.CCR-10-0984

52. Dziadkowiec KN, Gąsiorowska E, Nowak-Markwitz E, Jankowska A. PARP inhibitors: review of mechanisms of action and BRCA1/2 mutation targeting. Prz Menopauzalny. 2016;15:215–219.

53. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly (ADP-Ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–134. doi:10.1056/NEJMoa0900212

54. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov. 2012;2(12):1134–1149. doi:10.1158/2159-8290.CD-12-0120

55. Mateo J, Porta N, Bianchini D, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, Phase 2 trial. Lancet Oncol. 2020;21(1):162–174. doi:10.1016/S1470-2045(19)30684-9

56. FDA grants accelerated approval to rucaparib for BRCA-mutated metastatic castration-resistant prostate cancer. 2020. (Accessed May 21, 2020.https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate.

57. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Eng J Med. 2020;382(22):2091–2102. doi:10.1056/NEJMoa1911440

58. Yi J, Liu C, Tao Z, et al. MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer. EBioMedicine. 2019;43:225–237. doi:10.1016/j.ebiom.2019.03.027

59. Fang P, Madden JA, Neums L, Moulder RK, Forrest ML, Chien J. Olaparib-induced adaptive response is disrupted by FOXM1 targeting that enhances sensitivity to PARP inhibition. Mol Cancer Res. 2018;16(6):961–973. doi:10.1158/1541-7786.MCR-17-0607

60. Anders L, Ke N, Hydbring P, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell. 2011;20(5):620–634. doi:10.1016/j.ccr.2011.10.001

61. Yao S, Fan LY-N, Lam EW-F. The FOXO3-FOXM1 axis: a key cancer drug target and a modulator of cancer drug resistance. Semin Cancer Biol. 2018;50:77–89. doi:10.1016/j.semcancer.2017.11.018

62. Shukla S, Bhaskaran N, Maclennan GT, Gupta S. Deregulation of FoxO3a accelerates prostate cancer progression in TRAMP mice. Prostate. 2013;73(14):1507–1517. doi:10.1002/pros.22698

63. Yamaguchi H, Hsu JL, Hung MC. Regulation of ubiquitination-mediated protein degradation by survival kinases in cancer. Front Oncol. 2012;2:15. doi:10.3389/fonc.2012.00015

64. Liu Y, Ao X, Ding W, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17(1):104. doi:10.1186/s12943-018-0856-3

65. Wierstra I. FOXM1 (Forkhead box M1) in tumorigenesis: overexpression in human cancer, implication in tumorigenesis, oncogenic functions, tumor-suppressive properties, and target of anticancer therapy. Adv Cancer Res. 2013;119:191–419.

66. Wang X, Kiyokawa H, Dennewitz MB, Costa RH The Forkhead Box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proceedings of the National Academy of Sciences of the United States of America 2002;99:16881–16886.

67. Liao GB, Li XZ, Zeng S, et al. Regulation of the master regulator FOXM1 in cancer. Cell Commun Signal. 2018;16(1):57. doi:10.1186/s12964-018-0266-6

68. Khongkow P, Gomes AR, Gong C, et al. Paclitaxel targets FOXM1 to regulate KIF20A in mitotic catastrophe and breast cancer paclitaxel resistance. Oncogene. 2016;35(8):990–1002. doi:10.1038/onc.2015.152

69. Ho KK, McGuire VA, Koo CY, et al. Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin. J Biol Chem. 2012;287(2):1545–1555. doi:10.1074/jbc.M111.284224

70. Fernandez de Mattos S, Villalonga P, Clardy J, Lam EW-F. FOXO3a mediates the cytotoxic effects of cisplatin in colon cancer cells. Mol Cancer Ther. 2008;7(10):3237–3246. doi:10.1158/1535-7163.MCT-08-0398

71. Rader J, Russell MR, Hart LS, et al. Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma. Clin Cancer Res. 2013;19(22):6173–6182. doi:10.1158/1078-0432.CCR-13-1675

72. McGovern UB, Francis RE, Peck B, et al. Gefitinib (Iressa) represses FOXM1 expression via FOXO3a in breast cancer. Mol Cancer Ther. 2009;8(3):582–591. doi:10.1158/1535-7163.MCT-08-0805

73. Millour J, Constantinidou D, Stavropoulou AV, et al. FOXM1 is a transcriptional target of ERalpha and has a critical role in breast cancer endocrine sensitivity and resistance. Oncogene. 2010;29:2983–2995.

74. Yang N, Wang C, Wang Z, et al. FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells. Oncogene. 2017;36(24):3428–3440. doi:10.1038/onc.2016.490

75. Kwok JM, Myatt SS, Marson CM, Coombes RC, Constantinidou D, Lam EW. Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol Cancer Ther. 2008;7:2022–2032.

76. Pandit B, Gartel AL. New potential anti-cancer agents synergize with bortezomib and ABT-737 against prostate cancer. Prostate. 2010;70(8):825–833. doi:10.1002/pros.21116

77. Halasi M, Hitchinson B, Shah BN, et al. Honokiol is a FOXM1 antagonist. Cell Death Dis. 2018;9(2):84. doi:10.1038/s41419-017-0156-7

78. Millour J, de Olano N, Horimoto Y, et al. ATM and p53 regulate FOXM1 expression via E2F in breast cancer epirubicin treatment and resistance. Mol Cancer Ther. 2011;10(6):1046–1058. doi:10.1158/1535-7163.MCT-11-0024

79. Crumbaker M, Khoja L, Joshua AM. AR signaling and the PI3K pathway in prostate cancer. Cancers. 2017;9(12):34. doi:10.3390/cancers9040034

80. Mahajan NP, Liu Y, Majumder S, et al. Activated Cdc42-associated kinase Ack1 promotes prostate cancer progression via androgen receptor tyrosine phosphorylation. Proceedings of the National Academy of Sciences of the United States of America 2007;104:8438–8443.

81. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19(5):575–586. doi:10.1016/j.ccr.2011.04.008

82. de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized Phase II study evaluating Akt blockade with Ipatasertib, in combination with Abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin Cancer Res. 2019;25(3):928–936. doi:10.1158/1078-0432.CCR-18-0981

83. 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. doi:10.1158/0008-5472.CAN-15-0728

84. 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. doi:10.1158/2159-8290.CD-18-0830

85. Juric D, Castel P, Griffith M, et al. Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature. 2015;518:240–244.

86. Zoubeidi A, Gleave ME. Co-targeting driver pathways in prostate cancer: two birds with one stone. EMBO Mol Med. 2018;10(4):e8928. doi:10.15252/emmm.201808928

87. Yan Y, An J, Yang Y, et al. Dual inhibition of AKT-m TOR and AR signaling by targeting HDAC 3 in PTEN – or SPOP-mutated prostate cancer. EMBO Mol Med. 2018;10(4):e8478. doi:10.15252/emmm.201708478

88. Yuan C, Wang L, Zhou L, Fu Z. The function of FOXO1 in the late phases of the cell cycle is suppressed by PLK1-mediated phosphorylation. Cell Cycle. 2014;13:807–819.

89. Huang Z, Zhou W, Li Y, et al. Novel hybrid molecule overcomes the limited response of solid tumours to HDAC inhibitors via suppressing JAK1-STAT3-BCL2 signalling. Theranostics. 2018;8:4995–5011.

90. Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011;437:199–213.

91. Corn PG, Wang F, McKeehan WL, Navone N. Targeting fibroblast growth factor pathways in prostate cancer. Clin Cancer Res. 2013;19:5856–5866.

92. Nickols NG, Nazarian R, Zhao SG, et al. MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer. Prostate Cancer Prostatic Dis. 2019;22:531–538.

93. Klein EA, Assoian RK. Transcriptional regulation of the cyclin D1 gene at a glance. J Cell Sci. 2008;121:3853–3857.

94. Qie S, Diehl JA. Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 2016;94:1313–1326.

95. Formisano L, Lu Y, Servetto A, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10:1373.

96. Choi YJ, Kim HS, Park SH, et al. Phase II study of Dovitinib in patients with castration-resistant prostate cancer (KCSG-GU11-05). Cancer Res Treat. 2018;50:1252–1259.

97. Huynh H, Nguyen TT, Chow KH, Tan PH, Soo KC, Tran E. Over-expression of the mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: its role in tumor progression and apoptosis. BMC Gastroenterol. 2003;3:19.

98. Mukherjee R, McGuinness DH, McCall P, et al. Upregulation of MAPK pathway is associated with survival in castrate-resistant prostate cancer. Br J Cancer. 2011;104:1920–1928.

99. Mittnacht S, Paterson H, Olson MF, Marshall CJ. Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein. Curr Biol. 1997;7:219–221.

100. Drosten M, Sum EYM, Lechuga CG, et al. Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway. Proceedings of the National Academy of Sciences 2014;111:15155–15160.

101. Abbas T, Dutta A. p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer. 2009;9:400–414.

102. Pacheco J, Schenk E. CDK4/6 inhibition alone and in combination for non-small cell lung cancer. Oncotarget. 2019;10(6):618–619. doi:10.18632/oncotarget.26545

103. Lee MS, Helms TL, Feng N, et al. Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models. Oncotarget. 2016;7(26):39595–39608. doi:10.18632/oncotarget.9153

104. Maust JD, Frankowski-McGregor CL, Bankhead A, Simeone DM, Sebolt-Leopold JS. Cyclooxygenase-2 influences response to cotargeting of MEK and CDK4/6 in a subpopulation of pancreatic cancers. Mol Cancer Ther. 2018;17(12):2495–2506. doi:10.1158/1535-7163.MCT-18-0082

105. Romano G, Chen P-L, Song P, et al. A preexisting rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling. Cancer Discov. 2018;8:556–567.

106. Zhou X, Hao Q, Lu H. Mutant p53 in cancer therapy – the barrier or the path. J Mol Cell Biol. 2018;11(4):293–305. doi:10.1093/jmcb/mjy072

107. The Cell-Cycle CJ. Arrest and apoptotic functions of p53 in tumor initiation and progression. Cold Spring Harb Perspect Med. 2016;6(3):a026104–a. doi:10.1101/cshperspect.a026104

108. Pitolli C, Wang Y, Candi E, Shi Y, Melino G, Amelio I. p53-mediated tumor suppression: DNA-damage response and alternative mechanisms. Cancers. 2019;11.

109. Tanaka T, Watanabe M, Yamashita K. Potential therapeutic targets of TP53 gene in the context of its classically canonical functions and its latest non-canonical functions in human cancer. Oncotarget. 2018;9(22):16234–16247. doi:10.18632/oncotarget.24611

110. De Laere B, Oeyen S, Mayrhofer M, et al. TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2019;25(6):1766–1773. doi:10.1158/1078-0432.CCR-18-1943

111. Ecke TH, Schlechte HH, Schiemenz K, et al. TP53 gene mutations in prostate cancer progression. Anticancer Res. 2010;30:1579–1586.

112. Lehmann S, Bykov VJN, Ali D, et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30(29):3633–3639. doi:10.1200/JCO.2011.40.7783

113. Sriraman A, Dickmanns A, Najafova Z, Johnsen SA, Dobbelstein M. CDK4 inhibition diminishes p53 activation by MDM2 antagonists. Cell Death Dis. 2018;9(9):918. doi:10.1038/s41419-018-0968-0

114. Laroche-Clary A, Chaire V, Algeo M-P, Derieppe M-A, Loarer FL, Italiano A. Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas. J Hematol Oncol. 2017;10(1):123. doi:10.1186/s13045-017-0482-3

Source: OncoTargets and Therapy.
Originally published October 15, 2020.

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