Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

Li, Kailin; You, Jieqiong; Wu, Qian; Meng, Wen; He, Qiaojun; Yang, Bo; Zhu, Chengliang; Cao, Ji

doi:10.1016/j.apsb.2021.01.002

Cited by 16 publications

(10 citation statements)

References 111 publications

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“…Encouraging signs of disease stabilization with FCN-437c monotherapy were observed, notably in a participant with heavily pretreated NSCLC (treatment ongoing). This promising efficacy signal is consistent with preclinical data that suggest a synthetically lethal relationship between KRAS oncogenes and loss of CDK4 or CDK6, leading to the consideration of CDK4/6 targeting as a treatment strategy for KRAS mut tumors [ 45 , 46 ]. These data support further exploration of FCN-437c in larger cohorts of patients with advanced solid tumors, in combination with endocrine therapy (e.g., AIs, fulvestrant) or antitumor agents with different targets/mechanisms of action appropriate to the tumor of interest.…”

Section: Discussionsupporting

confidence: 76%

A Phase I Dose-Escalation and Dose-Expansion Study of FCN-437c, a Novel CDK4/6 Inhibitor, in Patients with Advanced Solid Tumors

Patnaik

Hamilton

Xing

et al. 2022

Cancers

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A phase I study evaluated the safety, tolerability, and maximum-tolerated dose (MTD)/recommended phase II dose (RP2D) of FCN-437c, a novel, orally available cyclin-dependent kinase inhibitor (CDK4/6i), in participants with advanced/metastatic solid tumors (aSTs). FCN-437c was escalated from 50 mg (once daily [QD] on days 1–21 of 28-day cycles) to the MTD/RP2D. In the dose-expansion phase, patients with CDK4/6i-treated breast cancer, or KRAS-mutant (KRASmut) non-small-cell lung cancer (NSCLC) received the MTD. Twenty-two patients were enrolled. The most common tumors in the dose-escalation phase (n = 15) were breast, colorectal, and lung (each n = 4 [27.3%]). The dose-expansion phase included five (71.4%) patients with breast cancer and two (28.6%) with KRASmut NSCLC. Twenty (90.9%) participants experienced FCN-437c–related adverse events. Dose-limiting toxicities occurred in two (33.3%) participants (200-mg dose, dose-escalation phase): grade 3 neutropenia and grade 4 neutrophil count decreased. Due to toxicities reported at 150 mg QD, the MTD was de-escalated to 100 mg QD. One (4.5%) participant (KRASmut NSCLC, 100-mg dose) achieved a partial response lasting 724+ days, and five (22.7%) had stable disease lasting 56+ days. In conclusion, FCN-437c was well tolerated with encouraging signs of antitumor activity and disease control. Further exploration of FCN-437c in aSTs is warranted.

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Section: Discussionsupporting

confidence: 76%

A Phase I Dose-Escalation and Dose-Expansion Study of FCN-437c, a Novel CDK4/6 Inhibitor, in Patients with Advanced Solid Tumors

Patnaik

Hamilton

Xing

et al. 2022

Cancers

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“…3 E) in MM cells. CDK4/6 are key initiators of the G1-to-S phase transition, while inhibition of CDK4/6 leads to G1 arrest of the cell cycle 26 , 27 . It was reported that inhibition of NAT10 induced cell cycle arrest in G1 phase and downregulated CDK4 expression 28 .…”

Section: Resultsmentioning

confidence: 99%

NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma

Wei

Cui

Min

et al. 2022

Acta Pharmaceutica Sinica B

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“…Cyclin D1 is a crucial gene that regulates the G1-S transition. 39 Complexes formed with Cyclin D1 and cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) promote cell cycle progression by inhibiting the retinoblastoma protein. 40 Furthermore, cyclin D1 expression can be inhibited by p21 and/or p27 through transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

KLF6 facilitates differentiation of odontoblasts through modulating the expression of P21 in vitro

Chen

et al. 2022

Int J Oral Sci

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Multiple signaling pathways are involved in the regulation of cell proliferation and differentiation in odontogenesis and dental tissue renewal, but the details of these mechanisms remain unknown. Here, we investigated the expression patterns of a transcription factor, Krüppel-like factor 6 (KLF6), during the development of murine tooth germ and its function in odontoblastic differentiation. KLF6 was almost ubiquitously expressed in odontoblasts at various stages, and it was co-expressed with P21 (to varying degrees) in mouse dental germ. To determine the function of Klf6, overexpression and knockdown experiments were performed in a mouse dental papilla cell line (iMDP-3). Klf6 functioned as a promoter of odontoblastic differentiation and inhibited the proliferation and cell cycle progression of iMDP-3 through p21 upregulation. Dual-luciferase reporter assay and chromatin immunoprecipitation showed that Klf6 directly activates p21 transcription. Additionally, the in vivo study showed that KLF6 and P21 were also co-expressed in odontoblasts around the reparative dentin. In conclusion, Klf6 regulates the transcriptional activity of p21, thus promoting the cell proliferation to odontoblastic differentiation transition in vitro. This study provides a theoretical basis for odontoblast differentiation and the formation of reparative dentine regeneration.

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Cyclin-dependent kinases-based synthetic lethality: Evidence, concept, and strategy

Cited by 16 publications

References 111 publications

A Phase I Dose-Escalation and Dose-Expansion Study of FCN-437c, a Novel CDK4/6 Inhibitor, in Patients with Advanced Solid Tumors

A Phase I Dose-Escalation and Dose-Expansion Study of FCN-437c, a Novel CDK4/6 Inhibitor, in Patients with Advanced Solid Tumors

NAT10 promotes cell proliferation by acetylating CEP170 mRNA to enhance translation efficiency in multiple myeloma

KLF6 facilitates differentiation of odontoblasts through modulating the expression of P21 in vitro

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