Table 10 Function of CDK4/6 based on cell line studies

Acute B lymphocytic leukemia

miR-142-3p/ HOXA5 axis, CyclinD1, CDK4, Bax and Caspase-3

Hmy2-cir, Nalm6 and HOXA5

↑↑ miR-142-3p: ↓ proliferation and ↑ G1 phase arrest via targeting HOXA5 and reducing CyclinD1 and CDK4 and promoting the expression of Bax and Caspase-3

[200]

Acute myeloid leukemia

CDK4/6, MAP-ERK and PI3K-AKT-mTOR signaling pathway, LC3B-I to LC3B-II

Kasumi-1, SKNO-1, ML-2, HL-60, HEL, MV4-11, NB-4, KG-1a, Kasumi-6, KG-1, KO52, MOLM-16, U937,

Kasumi-3, UF-1, CMK-86, MOLM-13, THP-1

and NOMO-1

Combination of CDK4/6 and autophagy inhibition: ↑ apoptosis

in t(8;21) AML cells

CDK4/6 inhibition: ↑ autophagy in t(8;21) AML cells

[194]

miR-335-3p/EIF3E axis and CDK4, Cyclin D1, Bcl-2, p21 and Bad

THP-1 and U937

↑↑ miR-335-3p: ↓ proliferation and ↑ cell cycle G0/G1 arrest and apoptosis via targeting EIF3E and reducing the Cyclin D1, CDK4, c-Myc expression and elevating P21 and Bad expression

[201]

miR-362-5p/ GAS7 axis and PCNA, CDK4, cyclin D1, and p21

TF-1, HL-60 and THP-1, HS-5

↑↑ miR-362-5p: ↑ proliferation via targeting GAS7 and increasing levels of PCNA, CDK4 and cyclin D1, but downregulating p21 expression

[202]

Bladder cancer

miR-124/CDK4 axis

HT1197, HT1376, J82, and 5637

↑↑ miR-124: ↓ growth and ↑ cell cycle arrest via targeting CDK4

[203]

miR-195/CDK4 axis

SV-HUC-1, 5637 and BIU-87

↑↑ miR-195: ↓ cell migration, invasion, cloning efficiency, and EMT process via targeting CDK4

[204]

miR-124/ CDK4 axis and E2F3, CDK4, Ki-67 and VEGF

Hek 293, SV-HUC-1, T24, 5637, J82 and UM-UC-3

↑↑ miR-124: ↓ cell viability, angiogenesis rate, proliferation, expression of E2F3, CDK4, Ki-67 and VEGF via targeting CDK4 and E2F3

↑↑ CDK4: ↓ miR-124 inhibition of cell viability, angiogenesis, and cell cycle

[205]

miR-1180-5p, p21, CDK4, CDK6, Cyclin D1 and Cyclin A2

Bladder cancer cell lines

↑↑ miR-1180-5p: ↓ proliferation via upregulating p21 and downregulating CDK4, CDK6, Cyclin D1 and Cyclin A2

[206]

CDK4/6 and FOXM1

RT112, J82, 253J, 5637, UM-UC-1 and RT4

CDK4/6 inhibition: ↓ FOXM1 phosphorylation

CDK4/6 inhibition showed synergy with CDDP

[195]

Breast cancer

CDK4/6, Hippo Pathway

MCF7, CAMA-1, HEK 293T, MCF7, T47D, and ZR-75–1

∆ FAT1: ↑ resistance to CDK4/6 inhibitors via the Hippo Pathway

[196]

CDK4/6, PI3Kα and PTEN

T47D and MCF7

∆ PTEN: ↑ cross-resistance to CDK4/6 and PI3Kα inhibitors via increased AKT activation

[172]

CDK4/6, AKT, cyclin D/CDK4-6/Rb and PI3K/AKT-mTOR pathways

MCF-7 and T47D, ZR-75-1, 182R-1, MPF-R,

Fulvestrant, CDK4/6i and AKTi triple combination: ↓ growth of breast cancer cells

∆ CDK4/6 and AKT: ↓ cyclin D/CDK4-6/Rb and PI3K/AKT-mTOR pathways

[207]

PI3Kα and CDK4/6, PD-1 and CTLA-4

HCC70, HCC1806, MDA-MB-468 and AT3OVA

Combination of PI3Kα and CDK4/6 inhibitors: ↑ apoptosis, cell-cycle arrest, and tumor immunogenicity

[208]

RB, Cyclin E, CDK2 and CDK4/6

MCF7 and T47D

Low levels of RB and high levels of Cyclin E were observed in CDK4/6 inhibitor-resistant cells

[98]

Wnt signaling pathway, MYC, and β-catenin

MDA-MB-231, CAL-148, MDA-MB-453, MDA-MB-157, MDA-MB-436, HCC1937, SUM149, MDA-MB-468, HEK293T

PARPi olaparib and the CDK4/6i palbociclib: ↓ HR during the G2 phase, ↓ tumour growth, ↓ MYC expression through the Wnt pathway, and ↑ DNA damage

[209]

CDK4/6-USP51-ZEB1 axis

MDA-MB-231, 293T, and SUM-159

∆ CDK4/6: ↓ tumor metastasis by destabilizing the ZEB1 protein

CDK4/6 stabilizes ZEB1 by phosphorylation and activation of USP51

[210]

CDK4/6, CCND1

MCF-7, ZR-75-1, and

HCC-1428

Combination of ZEN-3694 with CDK4/6 inhibition: ↓ proliferation and ↑ apoptosis

[211]

CDK4/6; HLA

MDA-MB-231 and MCF7, CAL-51, SK-BR-3, HCC1143, BT-474, MDA-MB-453, BT-20, T-47D, HCC1143, BT-549, Hs587T, HEK293, HEK293T, HFF-1, MCF 10 A, WI-38, IMR-90, and HeLa

CK1ε inhibition not only inhibits RB1 from degradation, but also inhibits CDK4/6i-induced CDK6 up-regulation via modulating SP1 protein stability, so increasing CDK4/6i efficacy

[212]

CDK4/6, Cyclin D1, HLA ligands (PSMC1)

MCF7 and T47D

Low-dose of CDK4/6 inhibitor: ↑ HLA class I surface expression in breast cancer cells

HLA ligands induced by CDK4/6i were found to be derived from proteins enriched in G1/S cell cycle transition

[213]

PI3K/mTOR signaling, CDK4/6-p-Rb signaling pathway

MCF7 and HCC1500, EFM19

Acquired resistance to CDK4/6 inhibitor monotherapy was found to be correlated with loss of dependence on pRb and induction of PI3K/mTOR signaling

Targeting PI3K/mTOR signaling dominates resistance to CDK4/6 inhibitors

[214]

Breast cancer

CDK4/6, HMGB1, TLR4 and NF-κB pathway

MCF‐7 and T47D

↑↑ HMGB1: ↑ tamoxifen resistance by combining with the TLR4 and NF-κB pathway

CDK4/6 inhibition: ↓ expression of HMGB1 and ↓ TLR4-NF-κB pathway, and in turn ↓ tamoxifen resistance

[215]

Cdk4/6 and TSC2 and mTORC1

MCF7

Cdk4/6 inhibition: ↓ proliferation partly via TSC2 and mTORC1

Cdk4/6 Regulates mTORC1 via the TSC

Cdk4/6 was found to phosphorylate TSC2, and in turn regulate mTORC1 via the TSC

[216]

CDK4/6 and PARP

MDA-MB-231 and SUM-159

CDK4/6 and PARP dual inhibitor, ZC-22: ↑ cell cycle arrest and ↑ DNA damage

ZC-22 was more effective than the combination of PARPi Olaparib and CDK4/6i Abemaciclib

[217]

CDK4/6, p21

MDA‐MB‐231 and MCF‐7

Abemaciclib and ABT-263 combination: ↓ viability of MDA-MB-231 cells, but not MCF-7 cell, and ↓ cytoplasmic p21 expression in MDA‐MB‐231 cells, ↑ caspase-dependent apoptosis in MDA-MB-231 cells

∆ p21: ↑ sensitivity of MCF‐7 cells to TRAIL

[218]

CDK4/6, CDK2, RB1

12 RB1 wild-type TNBC cell lines and one RB1 mutant cell line (BT549), MFM223 cell, MFM223pR cells, MES CAL51

LAR subtype of TNBC was found to be sensitive to CDK4/6 inhibitors

Cell lines with palbociclib sensitivity showed low post-mitotic CDK2 activity

The proliferative CDK2 high subpopulation had resistance to CDK4/6 inhibitors

[197]

Breast cancer

miR-124/CDK4 axis

MCF-7, Bcap-37, and MDA-

MB-435S

↑↑ miR-124: ↓ cell viability, proliferation, and cell cycle progression via targeting CDK4

[219]

miR-623, XRCC5, CDK4/6 and PI3K/AKT and Wnt/β-catenin signaling pathways

MDA-MB-453 and MCF7

↑↑ miR-449a/b: ↓ proliferation, migration, invasion and ↑ apoptosis via targeting XRCC5 and reducing CDK4/6

MiR-623 suppressed the activations of PI3K/AKT and Wnt/β-catenin signaling pathways induced by XRCC5

[220]

AFAP1-AS1/ miR-545/CDK4 axis

MDA-MB-231 and BT-549

AFAP1-AS1is involved in TNBC pathogenesis via regulating miR-545/CDK4 axis

[221]

MALAT1-miR-124-CDK4/E2F1 signaling pathway and CDK4

MCF-7, MDA-MB-435S, MDA-MB-231, ZR-75-1, HSS578T, HCC1937 and BCAP-37, and MCF-10A

↑↑ miR-124: ↓ proliferation and ↑ cell cycle G0/G1 phase arrest via targeting CDK4/E2F1 signaling pathway

MALAT1 was found to inhibit miR-124 and increase the expression of CDK4

[222]

miR-519d-3p

MDA-MB-231 and HCC1937

↑↑ miR-519d-3p: ↓ proliferation, colony formation, migration, invasion and ↑ G0/G1 phase via targeting LIMK1 and reducing expression of CDK4, 6/Cyclin D1, and CDK2/Cyclin E1

[223]

miR-1301-3p/ICT1 axis and CDK4, Cyclin D1, Bcl-2, p21, Bad and Bax

MCF-7, T-47D, MDA-MB-231,

MDA-MB-468, and

MCF-10A

↑↑ miR-1301-3p: ↓ proliferation, growth and ↑ G0/G1 phase arrest and apoptosis via targeting ICT1, and reducing the expression of CDK4, Cyclin D1, Bcl-2, but elevating p21, Bad and Bax levels

[224]

miR-200b-3p and miR-429-5p, cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, and LIMK1/CFL1 pathway

MDA-MB-231, HCC1937, MCF-7 and MCF-10

↑↑ miR-200b-3p and miR-429-5p: ↑ G2/M and G0/G1 cell cycle arrest via downregulating cyclin D1/CDK4/CDK6 and cyclin E1/CDK2, and ↓ proliferation, migration, and invasion via the LIMK1/CFL1 pathway

[225]

miR-34c, CCND1, CDK4 and CDK6

MDA-MB-231, MDA-MB-468, BT-549 and T47D

↑↑ miR-34c: ↓ proliferation and ↑ cell death and G2/M phase arrest via downregulating miR-34 targets CCND1, CDK4 and CDK6

[226]

Breast cancer and other solid tumors

CDK4/6

BT474, SKBR3, MDA-MB-361, MDA-MB-453, and MCF7, MMTV-PyMT-S2WTP3, B16-OVA, and CT-26

∆ CDK4/6: ↓ proliferation, ↑ anti-tumour immunity and cell cycle arrest

[198]

Cervical cancer

SCP3, AKT/cyclin D1–CDK4/6 signaling, NANOG and cyclin D1–CDK4/6/E2F1 axis

CaSki

SCP3 induces immune-resistant and stem-like features through AKT/cyclin D1–CDK4/6 signaling

SCP3 enhanced transcription of NANOG through the cyclin D1–CDK4/6/E2F1 axis

[199]

circ_0000326/miR-338-3p/CDK4 axis

Hela, Caski, SiHa, SW756 and C-33A

∆ circ_0000326: ↓ proliferation, migration and cell cycle progression via miR-338-3p/CDK4 axis

[227]

Clear cell renal cell carcinoma

miR-1, CDK4, CDK6, Caprin1 and Slug

ACHN, 786-O, SN12-PM6 and HK-2

↑↑ miR-1: ↓ proliferation, motility, migration and invasion via targeting CDK4, CDK6, Caprin1 and metastasis related gene Slug

[228]

DMDRMR, IGF2BP3, CDK4

786-O, 769-P, ACHN, and Caki-1, HK2, and HEK293T

DMDRMR enhanced the G1-S transition, and promotes cell proliferation via cooperating with IGF2BP3 to regulate target genes including CDK4 in an m6A-dependent manner

[229]

miR-206/ CDK4, CDK9 and CCND1 axis

ACHN, 786-O, SN12PM6 and HK-2

↑↑ miR-206: ↓ proliferation and ↑ cell cycle arrest via directly targeting cell cycle related gene CDK4, CDK9 and CCND1

[230]

Colorectal cancer

HAGLR/miR-185-5p/CDK4 and CDK6 axis

FHC, DLD-1, SW620 HCT-116, LOVO, and SW480

∆ HAGLR: ↓ proliferation, and ↑ apoptosis via regulating miR-185-5p/CDK4 and CDK6 axis

[231]

miRNA-20b-5p/ CCND1/CDK4/FOXM1 axis

HCT-116, SW480, and HT29, 293T cells, and 3T3

↑↑ miRNA-20b-5p: ↓ cell cycle, migration, and invasion in but had no effect on apoptosis via targeting CCND1 and regulating CCND1/CDK4/FOXM1 axis

[232]

MCM3AP-AS1/ miR-545/CDK4 axis

CR4

↑↑ MCM3AP-AS1: ↑ cell cycle progression and proliferation, ↓ G1 arrest via regulating miR-545/CDK4 axis

[233]

miR-142-3p/CDK4 axis

HEK293T, HT29 and SW116

↑↑ miR-142-3p: ↓ viability and colony formation and ↑ cell cycle arrest via targeting CDK4

[234]

miR-6883-5p and miR-149*, CDK4/6 and CDK4/6-FOXM1 signaling

HCT116, RKO, HT-29, and SW480

↑↑ miR-6883-5p and miR-149*: ↓ cell growth, ↑ G0-G1 phase cell-cycle arrest and ↑ apoptosis by partially targeting CDK4/6

MiR-6883-5p and miR-149* combinations: ↓ CDK4/6-FOXM1 signaling

[235]

miR-875-5p/ EGFR axis, cyclin D1, cyclin D2, CDK4, p57and p21

DLD1, HCT116, LOVO, RKO, LS174T, HCT8, HR28348, HT29, SW620, SW480 and NCM460

↑↑ miR-875-5p: ↓ cell proliferation, migration, invasion, and ↑ apoptosis via targeting EGFR and downregulating cyclin D1, cyclin D2, CDK4, Bcl2 and upregulating protein cleaved caspase-3, p57and p21

[236]

uc.77-/ miR-4676-5p/FBXW8/CDK4 axis

HCT116, HT-29, LoVo, and SW620

↑↑ uc.77-: ↓ proliferation and ↑ G0/G1 phase arrest via targeting miR-4676-5p and upregulating FBXW8, in turn FBXW8-mediated CDK4 Protein degradation

[237]

LINC00665, miR-126-5p, and cyclin D1, CDK4, Rb

DLD1, RKO, HCT116, LOVO, SW480 and NCM460

∆ LINC00665: ↓ proliferation and ↑ apoptosis via upregulating miR-126-5p, thus reducing cyclin D1, CDK4, Rb

[238]

miR-29a-3p/RPS15A axis and CDK4, Cyclin D1, p21, Bax and Bcl-2

DLD-1, RKO, SW480, and HCT116, and FHC

↑↑ miR-29a-3p: ↓ proliferation, ↑ cell cycle arrest and apoptosis via targeting RPS15A and regulating CDK4, Cyclin D1, p21, Bax and Bcl-2

[239]

Epithelial ovarian cancer

PCAT-1, cyclin D1 and CDK4

SKOV-3, OVCAR-3, HEY-A8, and HO8910-PM

∆ PCAT-1: ↓ proliferation, migration and invasion, but ↑ G0/G1 phase arrest via decreasing levels of cyclin D1 and CDK4

[240]

Esophageal cancer

miR-486/ CDK4/BCAS2 axis

KYSE150, EC9706 and TE-9, and Het-1A

↑↑ miR-486: ↓ colony formation, migration and invasion, ↑ G0/G1 phase arrest and apoptosis via targeting CDK4/BCAS2

[241]

miR-124/CDK4 axis

TE-1

↑↑ miR-124: ↓ tumor growth and ↑ apoptosis

[242]

Esophageal squamous cell carcinoma

miR-1/MET/cyclin D1/CDK4 axis

Het-1A, QBC939, HepG2, and 293T

↑↑ miR-1: ↓ proliferation, and ↑ apoptosis via targeting MET, cyclin D1, and CDK4

[243]

Ewing's sarcoma

CDK4/6, IGF1R and PI3K/mTOR signaling

A673, SKNEP1, SKNMC, CADOES1, TC32, SKPNDW, AEW541, and GDC0941

Combination of CDK4/6 and IGF1R inhibition: ↓ cell cycle progression and PI3K/mTOR signaling

[173]

DLX6-AS1/miR-124-3p/CDK4 axis

SK-ES-1, A673, RD-ES, and MSCs

∆ DLX6-AS1: ↓ proliferation, and ↑ apoptosis via regulating miR-124-3p/CDK4 axis

[244]

Gastric cancer

CDK4/6, PAK1, PDK1-AKT pathway,

SGC-7901 and MKN-45

CDK4/6 inhibition: ↓ cell viability and ↓ PAK1 expression

∆ PAK1: ↑ cell sensitivity exposed to CDK4/6 inhibitor and ↑ DNA damage

↑↑ PDK1: ↓ effect of PAK1 deletion on DNA damage ↓ sensitivity towards CDK4/6 inhibitor and ↓ cell cycle arrest caused by PAK1 depletion

[245]

miR-449a/b/CDK4/6, E2F1, and CDKs-pRb-E2F1 signaling pathway

BGC-823 and GES-1

↑↑ miR-449a/b: ↓ proliferation and migration and ↑ apoptosis via targeting CDK4 and CDK6

[246]

miR-1301-3p, SIRT1, Cyclin D1, CDK4, c-Myc, P21

GES-1, HEK-293T, SGC-7901 and MGC-803, CCK-8

↑↑ miR-1301-3p: ↑ proliferation and cell cycle progression via targeting SIRT1 and elevating the Cyclin D1, CDK4, c-Myc expression and reducing P21 expression

[247]

miR-486-5p, SMAD2, CDK4, and ACTR3

GC9811, GC9811-P, HMrSV5

↑↑ miR-486-5p: ↓ EMT process via reducing SMAD2, CDK4, and ACTR3

[248]

miR-34a, Bcl-2, CDK4, and cyclin D1

SGC-7901 cells

Curcumin: markedly ↑↑ miR-34a, ↓ proliferation, migration, and invasion, cell cycle progression in G0/G1-S phase and via downregulating the Bcl-2, CDK4, and cyclin D1 protein expression

[249]

miR-143/ DNMT3A axis and Cyclin D1, CDK4 and CDK6

MKN28, MKN-45, BGC-823, SGC-7901 and MGC803 and GES-1

↑↑ miR-143: ↓ proliferation, invasion, and cell cycle progression via targeting DNMT3A and reducing Cyclin D1, CDK4 and CDK6

[250]

RASSF1A/miR-711/CDK4 axis

SGC-7901

↑↑ RASSF1A: ↓ proliferation, viability, migration, invasion and ↑ G1 phase arrest via upregulating miR-711 and in turn downregulating CDK4

[251]

Linc-ROR/miR-212-3p/FGF7 axis and CDK4, CDK6, Cyclin D1, N-Cadherin, Vimentin, MMP-9, MMP-2, P21, P27, E-Cadherin, and CK-19

AGS and MGC-803

∆ Linc-ROR: ↓ proliferation, migration, and invasion via miR-212-3p/FGF7 axis and downregulating CDK4, CDK6, Cyclin D1, N-Cadherin, Vimentin, MMP-9, MMP-2, but upregulating of P21, P27, E-Cadherin, CK-19

[252]

Gastric cancer

miR-29a-3p, CDK2, CDK4, and CDK6

GES-1, SGC-7901, AGS, MCG803, and BGC-823

↑↑ miR-29a-3p: ↓ proliferation via downregulating the expression of CDK2, CDK4, and CDK6

[253]

GCRL1/miR-885-3p/CDK4 axis

SGC-7901, GES-1, MGC-803, BGC-823, and AGS

↑↑ GCRL1: ↑ proliferation, migration and invasion by targeting miR-885-3p, and positively regulating CDK4

[254]

Glioblastoma

CDK4/6, Rb1, and ↓ miR-17˜92 family, E2F cell cycle pathway

GSC lines

Palbociclib, CDK4/6 inhibitor: ↓ Rb1 phosphorylation and ↓ miR-17˜92 family and paralog expression in the sensitive PN GSC lines, and ↑ proneural-mesenchymal transition

[255]

CDK4/6, c-Met/TrkA-B pathways

G88 cells and GBM cells

Combination of CDK4/6 inhibitor, abemaciclib, with c-Met/Trk inhibitor, altiratinib: ↑ cell cycle arrest and ↑ cytotoxicity via enhanced apoptosis

[256]

miR-129/CDK4/6 and MDM2 axis

U87MG, 251, U87, and HEK293

↑↑ miR-129: ↓ cell cycle and growth via targeting CDK4/6 and MDM2 axis

[257]

Glioblastoma multiforme

miR-124-CDK4 axis

SWO-38 and U251

∆ CDK4: ↑ radiosensitivity

↑↑ miR-124: ↑ radiosensitivity via targeting CDK4

[258]

miR-138, EZH2, CDK6, E2F2, E2F3, and EZH2-CDK4/6-pRb-E2F1 pathway

NHA, 87MG, U251MG, A172, T98G,

U118 and SHG-44

↑↑ miR-138: ↓ proliferation but ↑ G1/S cell cycle arrest via directly targeting EZH2, CDK6, E2F2 and E2F3, and in turn blocked EZH2-CDK4/6-pRb-E2F1 loop

[259]

circMMP9/ miR-124/CDK4 and AURKA axis and eIF4A3

U251, SHG44, A172, SNB19 and U87

∆ circMMP9: ↓ proliferation, migration, and invasion vi regulating miR-124/CDK4 and AURKA axis

eIF4A3 was found to promote circMMP9 expression

[260]

Glioma

CDK4/6 and RB

U87, U251, H4, A172, and NHAs

∆ CDK4: ↓ colony formation and proliferation, and ↑ apoptosis and sensitivity to TMZ

RB phosphorylation mediated by CDK4 showed oncogenic function in glioma

Selective inhibitors of CDK4/6: ↓ proliferation and ↑ apoptosis

[261]

HMMR-AS1/ miR-7/CDK4 axis

LN229, T98 and A172

∆ HMMR-AS1: ↓ cell viability, invasion, and colony formation via upregulating miR-7 and reducing CDK4

Sevoflurane treatment: ↓ glioma cell progression via reducing HMMR-AS1 and increasing miR-7, thus downregulating CDK4

↑↑ miR-7: ↓ cell viability, invasion, and colony formation ability via reducing CDK4

[262]

H. pylori related gastric cancer

miR-101/ SOCS2 axis and c-myc, CDK2, CDK4, CDK6, CCND2, CCND3, and CCNE2, p14, p16, p21 and p27

GES-1, MKN45 and 7901

↑↑ miR-101: ↓ proliferation and colony formation and ↑ G1-phase arrest via targeting SOCS2 and downregulating c-myc, CDK2, CDK4, CDK6, CCND2, CCND3, and CCNE2

[263]

Head and neck mucosal melanoma

CDK4

ME OMM cell line

CDK4 knockdown in ME cells led to delayed

G1/S cell cycle phase transition

Abemaciclib and dacarbazine synergistically

inhibited ME cells

[264]

Head and neck squamous cell carcinoma

CDK4/6, mTOR and stat3 pathways, IL6-stat3 axis

Cal27, HSC3 and HSC6

Combination of CDK4/6 inhibitor, LY2835219, and metformin: ↑ cell cycle arrest and ↓ colony formation, viability, growth

SASP which is induced by LY2835219 could upregulate cancer stemness, but it can be attenuated in combination with metformin

[265]

Hepatocellular carcinoma

CDK4/6 and PI3K/AKT signaling pathway

Huh7, HepG2 and Hep3B

Aminoquinol, a new CDK4/6 and PI3K/AKT inhibitor: ↓ viability, ↑ apoptosis, and ↑ G1 phase arrest

[174]

CDK4/6-Rb-myc and mTORC1/p70S6K signaling

HepG2, HUH7, PLC/PRF-5, HEP3B

Combination of Palbociclib with Regorafenib: ↓ spheroid cell growth and ↓ cell migration/ and invasion, and ↑ cell death

The combination teraphy was found to be more effective than single treatments also under hypoxia

[266]

circ_0001588/miR-874/CDK4 axis

SK-Hep-1, Hep-3B, HepG2, BEL-7402, and MHCC-LM3, and LO2

∆ circ_0001588: ↓ proliferation, migration, and invasion vi regulating miR-874/CDK4

[267]

hsa_circ_0016788/miR-486/CDK4 axis

HepG2, Hep3B, Huh7, HCCLM3, MHCC97L, LO2

∆ hsa_circ_0016788: ↓ proliferation, invasion and ↑ apoptosis via regulating miR-486/CDK4 axis

[268]

miR-498/FOXO3 axis and Cyclin D, CDK4

HepG2 and Huh7

↑↑ miR-498: ↓ proliferation, migration, invasion, ↑ cell cycle arrest and apoptosis via inducing FOXO3 expression and regulating Cyclin D, CDK4

[269]

CCDC144NL-AS1/ miR-940/WDR5 axis and MMP2, MMP9, CDK1, CDK2, and CDK4

Huh-7, HepG2, Hep3B, SMMC-7721, MHCC97H, SNU-368, HCCLM3, and L02

↑↑ CCDC144NL-AS1: ↑ proliferation, invasion and ↓ apoptosis via miR-940/WDR5 axis

CCDC144NL-AS1 and WDR5 upregulated MMP2, MMP9, CDK1, CDK2, and CDK4 expression

[270]

miR-34a, p-p53, SIRT1, cyclin D1, CDK4, CDK6, BCL-2, MDR1/P-gp and AXL proteins

HepG2

miR-34a combined with treatment with doxorubicin: ↓ proliferation, viability, ↑ G1 phase arrest and apoptosis via downregulating expression levels of p-p53, SIRT1, cyclin D1, CDK4, CDK6, BCL-2, MDR1/P-gp and AXL proteins

[271]

miR-497, miR-195, CCNE1, CDC25A, CCND3, CDK4, and BTRC

Hep G2, Hep 3B, HLE, Huh7, JHH-4, and sK-Hep-1

↑↑ miR-497 and miR-195: ↓ cell growth and↑ G1 arrest

CCNE1, CDC25A, CCND3, CDK4, and BTRC were found to be direct targets for miR-497 and miR-195

[272]

circSP3/ miR-198/CDK4 axis

Hep-3B, Huh-7, Bel-7402, SMMC-7721 and HL-77O2

↑↑ circSP3: ↑ proliferation, migration and invasion via targeting miR-198 and inducing CDK4

[273]

VPS9D1-AS1/HuR/CDK4 signaling axis

HepG2

∆ VPS9D1-AS1: ↓ proliferation and colony formation but ↑ apoptosis

VPS9D1-AS1 was found to bind to the HuR protein and thus increase the stability and expression of the CDK4 mRNA

[24]

Kaposi’s sarcoma–associated herpesvirus

miR-34a-5p/ c-fos axis, CDK4/6, cyclin D1, MMP2, MMP9

SH-SY5Y and 293T

↑↑ miR-34a-5p: ↓ proliferation and migration, and ↑ G1 cell cycle arrest via targeting c-fos, thus down-regulating CDK4/6, cyclin D1, MMP2, MMP9

[274]

Leiomyosarcoma

CDK4/6, Rb

SK-LMS-1 and SK-UT-1

Palbociclib treatment: ↓ protein levels of Phospho-Rb, ↓ proliferation, and ↓ G0/G1-phase arrest with decreased S/G2 fractions in SK-LMS-1 but

SK-UT-1 did not respond

[275]

Lung cancer

CDK4/6 and PAKs

H157, H322, H1299, H2170, A427, HCC4006, H1648, HCC827, H1437, H1944, H2172 and HBEC

CDK4/6 and PAKs inhibitor combination: ↑ apoptosis

[276]

CDK4/6 and RB

H1975 and H1975OR

Combination of CDK4/6 inhibitor palbociclib and osimertinib: ↓ resistance of osimertinib

[277]

LINC01194/ miR-486-5p/CDK4 axis

A549, H1299, H460, H1975, and BES-2B

∆ LINC01194: ↓ proliferation, migration and invasion via regulating miR-486-5p/CDK4 axis

[278]

hsa_circ_0014235/miR-520a-5p/CDK4 axis

A549, H1299, and 16HBE

↑↑ hsa_circ_0014235: ↑ DDP chemoresistance, proliferation, migration and invasion via regulating miR-520a-5p/CDK4 axis

[279]

miR-613/CDK4 axis

HEK293T, A549 and SPCA1

↑↑ miR-613: ↓ cell viability and colony formation and cell cycle arrest via targeting CDK4

[280]

miR-34b-3p/CDK4 axis

A549, H1299, and BEAS‐2B

↑↑ miR-34b-3p: ↓ proliferation, ↑ cell cycle arrest and apoptosis via targeting CDK4

[281]

circRNA_001010/miR-5112/ CDK4 axis

A549

↑↑ circRNA_001010: ↑ proliferation, migration and invasion and ↓ apoptosis via regulating miR-5112/ CDK4 axis

[282]

miR-143, miR-506, CDK1, CDK4, and CDK6

H69-AR, Calu3, H358, and H1975

Combinatorial treatment with miR-143 and miR-506: ↓ CDK1, CDK4, and CDK6, cell cycle progression and ↑ apoptosis

[51]

miR-340/ CDK4 axis

A549, H1299, H460, and 16HBE

↑↑ miR-340: ↓ proliferation via targeting CDK4

[283]

miR-486-5p/CDK4 axis

BEAS-2B, A549, H1650, PC-9, 95-D and SPCA-1

∆ CDK4: ↓ proliferation, and ↑ apoptosis

↑↑ miR-486-5p: ↓ proliferation and cell cycle progression via targeting CDK4

[284]

miR-326, CCND1, cyclin D1, cyclin D2, CDK4, p57and p21

A549, SPC-A-1, H1299, SK-MES-1, 95D, and HELF

↑↑ miR-326: ↓ cell proliferation, migration, invasion, and ↑ apoptosis via targeting CCND1 and downregulating expression levels of cyclin D1, cyclin D2, CDK4 and upregulating of p57 and p21

[285]

miR-134/ CCND1 axis and cyclin D1, cyclin D2, CDK4, p57and p21

A549, SPC-A-1, H1299, SK-MES-1, NCI-H520, 95D, and HELF

↑↑ miR-134: ↓ cell growth, cell viability, colony formation, migration and invasion and ↑ apoptosis via targeting CCND1 and reducing cyclin D1, cyclin D2, CDK4 and up-regulation of p57and p21

[285]

miR-98, TWIST-

Akt-CDK4/CDK6 and

TWIST-Akt-bcl2/Bax pathways

A549 and NCI-H23

↑↑ miR-98: ↓ proliferation, invasion via inhibiting TWIST-

Akt-CDK4/CDK6 and ↑ apoptosis via activating

TWIST-Akt-bcl2/Bax pathway

[286]

miR-1290/ IRF2 axis and CDK2 and CDK4

A549, H1299, SPC-A1, H1970 and H460, and BEAS-2B

↑↑ miR-1290: ↑ proliferation, colony formation and invasion via targeting IRF2 and upregulating CDK2 and CDK4

[287]

circHIPK3/miR-124 axis and SphK1, STAT3 and CDK4

A549 and BEAS-2B

↑↑ circHIPK3: ↑cell survival and proliferation via targeting miR-124 and upregulating SphK1, STAT3 and CDK4

[288]

miR-593, SLUG/protein kinase B (Akt)/cyclin D1/CDK4 or CDK6 signaling pathway and SLUG/Akt/Bcl-2/BAX signaling pathway

A549, NCI-H1299, NCI-H358 and NCI-H1993

↑↑ miR-593: ↓ proliferation via inactivating the SLUG/protein kinase B (Akt)/cyclin D1/CDK4 or CDK6 signaling pathway

[289]

SART3, miR-34a, and CDK4/6

A549, HEK293T cells, H1299 and NTERA-2

SART3 overexpression: ↑ miR-34a levels, ↓ the miR-34a target genes CDK4/6, thus caused G1 phase arrest

[290]

LncSENCR/miR-1-3p/CDK4/6 axis

A549, SPC-A1,

H1299, H1650, H1975 and PC-9, and 16HBE

∆ lncSENCR: ↓ proliferation via targeting miR-1-3p and upregulating CDK4/6

[291]

miR-545, cyclin D1 and CDK4

A549, HFL1 and NCI-H460

↑↑ miR-545: ↓ proliferation but ↑ G0/G1 phase arrest and apoptosis via targeting cyclin D1 and CDK4

[292]

linc00703, cyclinD1 and CDK4

A549, H226, PC-9, H358 and BEAS-2B

↑↑ linc00703: ↓ proliferation, colony formation, but ↑ G1/G0 phase arrest and apoptosis via reducing expressions of cyclinD1 and CDK4

[293]

Lung cancer

circ_0007766 and Cyclin D1/Cyclin E1/CDK4 pathway

SPCA-1

∆ circ_0007766: ↓ proliferation, migration, but ↑ G0/G1 phase arrest and apoptosis via reducing expression of Cyclin D1/Cyclin E1/CDK4

[294]

Medulloblastoma

CDK4/6, PI3K, and FGFR

DAOYand UW228-3,

PI3K, FGFR, and CDK4/6 inhibition: ↓ viability and proliferation

PI3K, FGFR, and CDK4/6 inhibition and combination with irradiation could have positive effects

[295]

HOTAIR/miR-483-3p/CDK4 axis

Daoy and D341

∆ HOTAIR: ↓ proliferation, and ↑ apoptosis via regulating miR-483-3p/CDK4 axis

[296]

miR-221-3p/ EIF5A2 axis and CDK4, Cyclin D1, Bcl-2 and Bad

D341: No. HTB-185; D283 Med: No. HTB-187, and DAOY

↑↑ miR-221-3p: ↓ proliferation and ↑ G0/G1 arrest and apoptosis via targeting EIF5A2 and downregulating CDK4, Cyclin D1 and Bcl-2 and increasing Bad expression

[297]

Melanoma

CDK4/6, PRMT5-MDM4 axis

A375, HT144, CHL1, MCF7, MDA-MB-231, HS578T, and HEK293T, C002, D04, A11, and C067

∆ CDK4/6 and PRMT5: ↑ efficacy of palbociclib in both naive and resistant models and ↓ emergence of resistance

[298]

CDK4/6 and p53 pathway

WM266.4 and A375 BRAF mutant melanoma cells

∆ CDK4/6: ↑ mitochondrial metabolism in BRAF V600 melanoma via a p53 dependent pathway

[299]

MEK, CDK4/6, NRAS, BRAF

WM3629, WM3670, WM3060, WM1366, D04, Sk-Mel-2, MM485, MM415, MaMel27II, A375, A2058, Sk-Mel28, MM466, and MaMel30I

Combination of MEK/CDK4,6 inhibitors: ↓ cell viability in a number of NRAS mutant melanoma cells and ↓ tumor growth in BRAF mutant and ‘wild-type’ melanoma cell lines

[300]

CDK4/6, VEGF-A

518A2 and LNM1

∆ CDK4 or CDK6: ↓ proliferation and migration, ↓ VEGF-A expression and ↓ stimulation of endothelial cell growth

CDK4/6 inhibition: ↓ proliferation and ↓ angiogenesis

[301]

CDK4/6, MEK

Mouse D4M3.A, Human SKMEL207

CDK4/6i alone and in combination with MEKi could enhance expression of CD137L, a T-cell costimulatory molecule on immune cells

MEK inhibition: ↓ phospho-ERK1/2

CDK4/6 inhibition: ↓ phospho-RB1 amounts

[302]

Melanoma

CDK4/6, RTK-RAS-RAF and RTK-PI3K-AKT pathways and NRAS

Hs936T, Hs944T, MELJUSO, SKMEL30, IPC298, SKMEL-2

NRAS-mutant melanomas showed resistance to genetic ablation of NRAS or combination MEK1/2 and CDK4/6 inhibition

[303]

hsa_circ_0025039/ miR-198/CDK4 axis

HEMn, A375, SK-MEL-1, A2058 and 293T cell

∆ hsa_circ_0025039: ↓ proliferation, colony formation, invasion and glucose metabolism via regulating miR-198/CDK4 axis

[304]

miR-206, CDK4, Cyclin D

A375, MALME-3M, RPMI7951, SK-

MEL-2, and SK-MEL-5

↑↑ miR-206: ↓ proliferation, migration, invasion, but ↑ G0/G1 phase arrest via targeting CDK4, Cyclin D

[305]

Multiple myeloma

Lnc-Pvt1/miR-486/ CDK4 and BCAS2 axis

CI-H929, U-266, LP-1 and RPMI-8226 and human normal plasma cells

∆ Lnc-Pvt1: ↓ proliferation, invasion and ↑ apoptosis via regulating miR-486/ CDK4 and BCAS2 axis

[306]

miR-338-3p/CDK4 axis

NCI-H929, MM1S, U266, and RPMI-8266

↑↑ miR-338-3p: ↓ proliferation, cell cycle progression, but ↑ apoptosis via targeting CDK4

[307]

Myxoid liposarcoma

FUS-CHOP/miR-486/CDK4 axis

1955/91 cells

∆ FUS-CHOP: ↓ growth, and ↑ apoptosis via regulating miR-486/CDK4 axis

[308]

Nasopharyngeal carcinoma

CDK4/c-Myc/miR-16/CCND1 pathway

5-8F and HONE1

∆ CDK4: ↓ expression of c-Myc, whish suppresses the miR-16 expression

↑↑ miR-16: ↓ CDK4 expression by repressing CCND1

[309]

miR-539/CDK4 axis

HEK293T, SUNE-1 and CNE-1

↑↑ miR-539: ↓ cell growth and ↑ cell cycle arrest via targeting CDK4

[310]

RP11-624L4.1 and CDK4/6-Cyclin D1-Rb-E2F1 pathway

NP69, CNE1, CNE2, 6-10B, 5-8F, HNE3, and C666-1

↑↑ RP11-624L4.1: ↑ proliferation via the CDK4/6-Cyclin D1-Rb-E2F1 pathway

[61]

Oral squamous cell carcinoma

MMP1, miR-188-5p, and CDK4 SOX4 axis

Tca8113 and HEK-293T

↑↑ MMP1: ↑ growth, motility, migration and invasion via regulating miR-188-5p, and CDK4 SOX4 axis

[311]

miR-198/CDK4 axis

Cal-27, SCC-9, SCC-25, and HaCaT

↑↑ miR-198: ↓ proliferation, invasion, EMT process, and ↑ apoptosis via targeting CDK4

[312]

miR-519d-3p/ CCND1 axis, CDK4, CDK6

CAL-27 and HN-6

↑↑ miR-519d-3p: ↓ cell viability and proliferation, ↑ G0/G1 phase arrest via targeting CCND1 and downregulating the expressions of CDK4, CDK6

[313]

miR-9 and CDK 4/6 pathway

Tca8113

↑↑ miR-9: ↓ cell growth, migration and colony formation, and ↑

cell arrest and apoptosis via CDK 4/6 pathway

CDK6 was found to be a target of miR-9

[314]

Osteosarcoma

miR-590-3p/ CDK4 axis

SaOS2, U2OS, MG63 and HOS

↑↑ miR-590-3p: ↓ proliferation via partially decreasing CDK4

[315]

miR-338-3p, RUNX2, CDK4 and MAPK pathway

MG-63, U2OS and hFOB

↑↑ miR-338-3p: ↓ cell viability and colony formation, migration, and invasion, but ↑ apoptosis via targeting RUNX2 and CDK4 and inhibiting the MAPK pathway

[316]

91 H, CDK4, Cyclin D1, and PCNA

MG63 and U2OS

∆ 91 H: ↓ proliferation, migration and invasion, but ↑ apoptosis via inducing methylation of CDK4 promoter and downregulating Cyclin D1, PCNA and CDK4

[317]

Ovarian cancer

CDK4/6

CD8 + T cells and B cells

CDK4/6 inhibition and anti-PD-1 antibody: ↑ efficacy of anti-PD-1 therapy and immune infiltration

[318]

LRRC75A-AS1-hsa-miR-330-5p/CDK4/6 axis, IFN-γ, ISG response, and STING pathway

OVCAR3 and HOC7

Palbociclib: ↑ secretion of IFN-γ and ↑ ISG response, ↑ expression of antigen-presenting molecules; via STING pathway

LRRC75A-AS1-hsa-miR-330-5p/CDK4/6 axis is involved in inhibiting the immune response of OC patients

[319]

CDK4/6-p-Rb signaling pathway, COL6A3

OCSPCs, epi-OCSPCs, msc-OCSPCs, SKOV3, ES2TR and ES2

∆ COL6A3: ↓ expression of DNMT1, CDK4, CDK6, and p-Rb and ↓ formation, invasion, tumor growth, and metastasis

[320]

CDK4/6 and PARP

OVCAR5 and SKOV3

CDK4/6 and PARP dual inhibitor, ZC-22: ↑ cell cycle arrest and ↑ DNA damage

The efficacy of ZC-22 was found to be higher than the combination of PARPi Olaparib and CDK4/6i Abemaciclib

[217]

miR-506-CDK4/6-FOXM1 axis

SKOV3, HeyA8

↑↑ miR-506: ↓ proliferation via targeting CDK4/6-FOXM1 axis

[321]

Pancreatic Adenocarcinoma

CDK4/6

Mia-Paca-2, Hs766t and PL-45

∆ CDK4/6: ↑ defective DNA repair by homologous recombination after chromosomal damage

[322]

CDK4/6-E2 F1 signaling pathway, MAGED1, FBP1

PANC-1 and BxPC-

PD0332991, CDK4/6 inhibitor, was found to stabilize FBP1 to hinder aerobic glycolysis

MAGED1, the key mediator in the CDK4-induced destabilization of

FBP1, was repressed by PD0332991

[323]

CDK4/6, MEK, ERK and Rb

BxPC-3, MiaPaCa-2, Panc-1, CFPAC, Panc 10.05, HPNE-KRAS, and HPNE

Combination of MEK and CDK4/6 inhibition: ↓ ERK and Rb phosphorylation and ↓ proliferation

[324]

Pancreatic cancer

miR-143, miR-506, CDK1, CDK4, and CDK6

HFL-1, MIA-Paca-2, and Panc-1

Combinatorial treatment with miR-143 and miR-506: ↓ CDK1, CDK4, and CDK6, cell growth

[51]

miR-196a/ NFKBIA axis and Cyclin D1 and CDK4/6

PANC-1, Capan-2, BxPC-3, SW1990, and H6C7

∆ miR-196a: ↓ proliferation, due to G0/G1 arrest via downregulating Cyclin D1 and CDK4/6 expression and ↓ migration

NFKBIA was a direct target of miR-196a

The expressions of Cyclin D1 and CDK4/6 were increased after silencing NFKBIA

[325]

Papillary thyroid cancer

miR-1256/HTR3A axis and CDK4 and Cyclin

D, and p21

TPC-1, B-CPAP and GLAG-66 and

Nthy-ori-3–1

↑↑ miR-1256: ↓ proliferation and ↑ cell cycle G0/G1 phase arrest via targeting HTR3A and regulating CDK4 and Cyclin

D, and p21

[326]

Prostate cancer

miR-3619-5p/CDKN1A axis and cyclin D1, CDK4/CDK6 and p21

DU145, PC3, LNcaP and RWPE-1

↑↑ miR-3619-5p: ↓ cell growth via activating p21 expression

miR-3619-5p induces CDKN1A expression via directly interacting the promoter, thus regulates prostate cancer cell cycle-associated genes including cyclin D1, CDK4/CDK6

[327]

miR-96/ FOXF2 axis and CyclinA1, CDK2 and CDK4

LNCaP, PC-3 and DU-145

∆ miR-96: ↓ proliferation and cell cycle progression via upregulating FOXF2 and downregulating CyclinA1, CDK2 and CDK4

FOXF2 was a direct target of miR-96

[328]

NR2F2-AS1 and CDK4

22Rv1

↑↑ NR2F2-AS1: ↑ proliferation and cell cycle progression via upregulating CDK4

[329]

Skin cancer

CDK4/6, Rb, cyclin D

A431 and A375

CDK4/6 inhibitor, Rafoxanide: ↓ viability, expression of CDK4/6, Rb, cyclin D, pho-CDK4/6 and pho-Rb, and ↑ G1 phase arrest and apoptosis

[330]

Uveal melanoma

RB, HGF, CDK4/6

UM001, UM002B, and UM004

Abemaciclib, CDK4/6 inhibitor: ↑ G1 arrest and ↓ cell growth in

Merestinib and Abemaciclib combination: ↓ HGF-mediated protection from cellular senescence

HGF decreased the growth-inhibitory effect of Abemaciclib

[331]

CDK4/6, MEK-ERK signaling pathway, OxPhos pathway

UM001, UM004, OMM1.3, WM3618F, and 92.1 cells

Combination of MEK plus CDK4/6 inhibition: ↓ cell cycle arrest but does not induce apoptosis

Upregulation of OxPhos pathway was observed in both MEKi-resistant tumors and CDK4/6i-tolerant tumors

[332]