Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives
Abstract
:Simple Summary
Abstract
1. Introduction
2. The Role of CDK4 and CDK6 in the Control of Cell Cycle Progression
3. Non-Cell Cycle Dependent Activities of CDK4 and CDK6
4. Mechanism of Action of CDK4/6 Inhibitors
5. Expression of CDK4 and CDK6 Containing Complexes in Ovarian Cancer
6. Combination Strategies of CDK4/6 Inhibitors with Conventional Cytotoxic Agents
7. Use of CDK4/6 Inhibitors as Single Agents in Ovarian Cancer Patients
8. Clinical Experiences on the Use of CDK 4/6i with Chemotherapy
9. CDK4/6 Inhibitors Safety and Tolerability Profile
10. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Cyclin/CDK | Palbociclib | Ribociclib | Abemaciclib |
---|---|---|---|
cycD1/CDK4 | 11 nM | 10 nM | 2 nM |
cycD3/CDK4 | 9 nM | ||
CDK6 | 15 nM | 39 nM | 9.9 nM |
cycA-E/CDK2 | >20 mM | >50 mM | 0.5 mM |
cycT1/CDK9 | NR | NR | 57 nM |
p25/CDK5 | >40 mM | >10 mM | 0.3 mM |
Gene (Protein) | Histotype | Number of Cases | Technique Used | Notes | Ref |
---|---|---|---|---|---|
CCND1 (cyclin D1) | EC, CCC, MC, SOC, Poorly differentiated | 43 | IHC | Overexpression in 26% of borderline and low-grade tumor samples | [51] |
EC, CCC, MC, SOC, Mixed | 81 | IHC, Western blot, RFLP-PCR | Amplification and overexpression not related to tumor stage or patients’ survival | [52] | |
Benign, Borderline, EC, CCC, MC, SOC, Undifferentiated | 79 | IHC | High-level of Cyclin D1 in borderline and low grade tumors | [53] | |
Serous EOC | 134 | IHC | Increased expression predicts shorter OS. Inverse correlation between CCND1 and CDKN1B expression | [54] | |
EC, MC, SOC, Undifferentiated, other | 65 | Southern and, Northern blot | Increased expression in 18% of cases; no impact on PSF | [55] | |
Advanced serous EOC | 66 | IHC | High expression predicts shorter patients’ PSF and OS | [56] | |
LGSOC (n = 26) HGSOC (n = 34) | 60 | IHC | Expressed in 67% of HGSOC samples. Expression predicts shorter OS | [57] | |
LGSOC (n = 27) HGSOC (n = 23) | 50 | IHC | Upregulation observed in HGOSC and FIGO stage III; high expression predicts shorter patients’ OS | [58] | |
EOC | 1307 | GEP | mRNA expression not related to patients’ survival | [27] | |
CCND2 (cyclin D2) | EC, GCT, SOC, Normal OV | 24 | RT-PCR | mRNA overexpressed in GCT | [59] |
GCT | 78 | RT-PCR IHC | Protein overexpressed in 42% of analyzed samples | [60] | |
EC, CCC, MC, SOC | 71 | MS-PCR | Promoter hyper-methylation associated with advance stage, residual tumor size, and shorter PSF | [61] | |
Well, moderate poor differentiated | 92 | RT-PCR | Higher expression in tumors respect to normal tissues | [62] | |
CCND3 (cyclin D3) | EC, CC, MC, SOC, poorly differentiated | 109 | IHC | Expression decreased in high grade/high stage tumors; absent expression predicts poor survival | [63] |
EOC | 1307 | GEP | High mRNA expression predicts shorter patients’ survival | [27] | |
CCNE1 (cyclin E1) | Benign, Borderline, SOC, MC, EC, CCC Undifferentiated | 103 | IHC, Western blot | High expression predicts shorter patients’ OS | [64] |
Serous EOC | 134 | IHC | Overexpression increased with tumor grade | [54] | |
SOC, MC, EC, CCC | 88 | IHC, FISH | Amplification associated with higher tumor grade and stage predicts shorter patients’ PSF and OS | [65] | |
Serous EOC | 172 | RT-PCR | High expression predicts shorter patients’ OS | [66] | |
Normal, Benign, SOC, MC, EC, CCC | 117 | IHC | Overexpression in 40% of analyzed tumors | [67] | |
HGSOC | 140 | FISH IHC | High expression predicts shorter patients’ OS | [68] | |
HGSOC STIC | 80 | IHC, FISH | Amplification was higher in HGSOC than STIC | [69] | |
CCC, EC, SOC | 207 | IHC, FISH | Amplification and overexpression associated with worse outcome in stage I tumor | [70] | |
HGSOC | 262 | ISH, IHC | Amplification and higher expression predict shorter patients’ OS | [71] | |
HGSOC | 40 | IHC | No relation between CCNE1 level and response neoadjuvant chemotherapy | [72] | |
HGSOC | 110 | IHC | High expression predicts platinum resistance and shorter patients’ OS | [73] | |
HGSOC | 48 | CISH, IHC, Nanostring digital PCR | Amplification and higher expression predict shorter patients’ OS | [74] | |
CCNE2 (cyclin E2) | EOC | 172 | RT-PCR | Amplification and expression had no significant impact on clinical outcome | [66] |
CDK2 | SOC, MC, EC, Undifferentiated | 108 | Southern blot RT PCR | Amplification in 6.4% of analyzed samples | [75] |
Benign, Borderline, SOC, MC, CCC, EC, Undifferentiated | 103 | IHC, Western blot, | High expression correlated with high tumor stage and predicts shorter patients’ OS | [64] | |
CDK4 | EC, MC, SOC, Undifferentiated, other | 48 | Southern and Northern blot | Not amplified in the analyzed tumors | [55] |
Benign, Borderline, SOC, MC, EC, CCC, Undifferentiated | 103 | IHC, Western blot | Overexpressed in malignant tumors. Overexpression associated with low CDKN2A expression and shorter OS | [76] | |
EOC | 1307 | GEP | mRNA expression not related to patients’ survival | [27] | |
CDK6 | EOC | 30 | IHC, RT-PCR | Upregulated in tumors compared to adjacent normal tissue | [77] |
EOC | 1307 | mRNA | High mRNA expression predicts shorter patients’ survival | [27] | |
HG-EOC | 73 | IHC, Western blot | Overexpression in 74% of analyzed tumors | [27] | |
SOC, MC, EC, CCC, Mixed Undifferentiated | 223 | IHC | High expression in 80% of analyzed tumors. Prevalent cytoplasmic localization | [78] | |
CDKN1A (p21WAF1) | EC, CCC, MC, SOC, Mixed | 316 | IHC | Low expression predicts shorter OS in older patients | [79] |
EC, CCC, MC, SOC, Mixed Undifferentiated | 106 | IHC | Higher expression in early stage tumor (FIGO I /II), associated with no tumor recurrence | [80] | |
EC, CCC, MC, SOC, NOSa, Others | 267 | IHC | Higher expression in in p53 WT samples predicts longer patients’ OS | [81] | |
EC, CCC, MC, SOC, Anaplastic | 129 | IHC, | Expression higher in CCC lower in MC; no relation with tumor grade, stage or survival | [82] | |
CDKN1B (p27KIP1) | Serous Non-serous | 88 | IHC RT-PCR | Lower nuclear staining and mRNA level in tumor compared to normal tissue; expression associated with lower stages, good prognosis and better response to chemotherapy | [83] |
Not-specified | 200 | RT-PCR Western blot | Down-regulation of p27 in tumor compared to normal tissues | [84] | |
CDKN2A (p16INK4A) | EC, SOC, MC, CCC, Mixed, Undifferentiated | 263 | IHC | Low expression predicts shorter patients’ OS | [85] |
HGSOC LGSOC | 106 | IHC | Increased expression of p16INK4A in high grade ovarian tumors | [86] | |
EC, SOC, MC, CCC, Mixed, Undifferentiated | 190 | IHC | High expression in malignant tumors related to shorter patients’ OS | [87] | |
EC, SOC, MC, Transitional cell, Undifferentiated | 300 | IHC | Low expression predicts shorter patients’ OS | [88] | |
CDKN2B (p15INK4B) | Serous EOC | 52 | MS-PCR RT-PCR | Promoter hyper-methylation and lower mRNA expression in cancer compared to normal | [89] |
EC, SOC, MC, CCC, EC, Brenner, GCT | 75 | MS-PCR | Promoter hyper-methylation in CCC samples | [90] | |
CDKN2C (p18INK4C) | GCT | 15 | RT-PCR | Expressed in all tumors, without any relation to clinic-pathological factors | [91] |
CDKN2D (p19INK4D) | EC, CCC, SOC, Undifferentiated Mixed | 445 | IHC RT-PCR | High expression in advanced tumor grade or stage associated with shorter patients’ OS | [92] |
Title | Phase | Population | Intervention | Primary Endpoint (s) | Status | NCT |
---|---|---|---|---|---|---|
Palbociclib With Cisplatin or Carboplatin in Advanced Solid Tumors | I | Solid neoplasms including ovarian cancer | Cisplatin on day 1 and palbociclib on days 2–22. Treatment repeats every 28 days. | Incidence of adverse events; incidence of DLT; RP2D | R | NCT02897375 |
PF-07104091 as a Single Agent and in Combination Therapy | I/II | Platinum resistant ovarian cancer, advanced breast cancer; NSCLC, SCLC | PF-07104091 (CDK2 inhibitor) administered orally alone or in combination with palbociclib and letrozole. | Incidence of adverse events; incidence of DLT | R | NCT04553133 |
Ribociclib with Platinum-based Chemotherapy in Recurrent Platinum Sensitive Ovarian Cancer | I | Recurrent platinum sensitive ovarian cancer | Participants will receive 200, 400, or 600 mg of ribociclib per day in combination with carboplatin + paclitaxel. Subjects will receive 6 cycles of carboplatin + paclitaxel given weekly with ribociclib. | MTD | NR | NCT03056833 |
Ribociclib and Gemcitabine Hydrochloride in Treating Patients With Advanced or Metastatic Solid Tumors | I | Advanced solid neoplasms | Patients receive gemcitabine hydrochloride on days 1 and 8 and ribociclib on days 8–14. Courses repeat every 21 days. | MTD | NR | NCT03237390 |
Testing the Addition of Abemaciclib to Olaparib for Women With Recurrent Ovarian Cancer | I | Platinum-resistant ovarian cancer | Patients receive olaparib on days 1–28 and abemaciclib on days 8–28 of cycle 1 and days 1–28 of subsequent cycles. Cycles repeat every 28 days. | RP2D | NYR | NCT04633239 |
Abemaciclib for the Treatment of Recurrent Ovarian or Endometrial Cancer | II | Hormone receptor positive recurrent ovarian or endometrial cancers | Patients receive abemaciclib on days 1–28. Patients with tumors that are hormone receptor positive also receive and anastrozole or letrozole per standard of care. Cycles repeat every 28 days. | Progression-free survival | NYR | NCT04469764 |
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Dall’Acqua, A.; Bartoletti, M.; Masoudi-Khoram, N.; Sorio, R.; Puglisi, F.; Belletti, B.; Baldassarre, G. Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives. Cancers 2021, 13, 3035. https://doi.org/10.3390/cancers13123035
Dall’Acqua A, Bartoletti M, Masoudi-Khoram N, Sorio R, Puglisi F, Belletti B, Baldassarre G. Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives. Cancers. 2021; 13(12):3035. https://doi.org/10.3390/cancers13123035
Chicago/Turabian StyleDall’Acqua, Alessandra, Michele Bartoletti, Nastaran Masoudi-Khoram, Roberto Sorio, Fabio Puglisi, Barbara Belletti, and Gustavo Baldassarre. 2021. "Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives" Cancers 13, no. 12: 3035. https://doi.org/10.3390/cancers13123035