Table 1.

Progress in combination therapy strategies of CDK4/6 inhibitors

Name of CDK4/6 inhibitor	Combined inhibitor type	Inhibitor name	Combined effect/mechanism	Cancer species	References
CDK4/6 inhibitor and chemotherapy
Palbociclib/G1T28 (Trilaciclib)/LY2835219	Microtubule protein inhibitor	Paclitaxel	Reduce the death of hematopoietic stem cells; Induce apoptosis; Enhance the efficacy of chemotherapy	ER+ breast cancer, TNBC, lung cancer	[74-77]
Ribociclib/PD-0332991	-	Cisplatin	Relieve kidney injury; Block proliferation; Induce apoptosis; Reverse chemotherapy resistance	Non-small cell lung cancer	[78-80]
CDK4/6 inhibitor and endocrine therapy
Abemaciclib	Selective estrogen receptor modulators (SERMs)	Tamoxifen	Inhibition of HMGB1 reversed drug resistance in endocrine therapy	ER+ breast cancer	[82]
Palbociclib	Selective estrogen receptor down-regulation (SERDs)	Fulvestrant	Prolong OS	Advanced breast cancer	[84-86]
Palbociclib	Aromatase inhibitor (AI)	Letrozole	Prolong PFS	ER+/HER2- breast cancer	[83]
CDK4/6 inhibitor and targeted therapy
CDK4/6 inhibitor +PARP inhibitor
Palbociclib/Abemaciclib	PARP inhibitor	Olaparib	Inhibit differentiation, induce apoptosis, and block proliferation	Prostatic cancer	[90]
Ribociclib (LEE011)/Palbociclib (PD0332991)		Olaparib	Inhibit PARP1 expression and damage DNA damage repair	Lung cancer	[91]
Palbociclib		Olaparib	Overcoming drug resistance of PARP inhibitors	TNBC	[92]
CDK4/6 inhibitor and other kinase inhibitors
Abemaciclib	EGFR inhibitor	Osimertinib	Prevent EGFR inhibitor resistance	Non-small cell lung cancer	[94]
Palbociclib		Osimertinib	Inhibit RB1 phosphorylation, block proliferation, and overcome EGFR inhibitor resistance		[95]
SHR6390	EGFR and HER-2 dual inhibitors	Pyrotinib	Overcome the drug resistance of EGFR and HER-2 double inhibitors	Gastric cancer	[96]
		Pyrotinib	Block proliferation, migration, and invasion, and prolong recurrence time	Breast cancer	[97]
Abemaciclib	PI3K inhibitor	Alpelisib	Suppress tumor progression	HER2+ breast cancer	[98]
Palbociclib	AKT inhibitor	Capivasertib	Inhibit tumor progression and metastasis		[99]
Ribociclib	CK1ε	D4476	Down-regulate CDK6 expression and overcome CDK4/6 inhibitor resistance	ER+/HER2- breast cancer	[100]
Ribociclib	WEE1 inhibitor	AZD1775/Adavosertib	Block proliferation, induce apoptosis, and overcome drug resistance of CDK4/6 inhibitors	ER+ breast cancer	[53]
Palbociclib	TTK inhibitor	CFI-402257	Overcome drug resistance of CDK4/6 inhibitors	ER+ breast cancer	[21]
	Aurora kinase A/B inhibitor	Aliserlib/Baraserlib
CDK4/6 inhibitor and epigenetic inhibitor
Palbociclib	DNMT target	-	Inhibit p16, inhibit tumor progression	Lung cancer	[104]
Palbociclib	EZH2 target	AC1Q3QWB	Arrest proliferation	glioblastoma	[107,108]
-	PRMT target	-	Prevent CDK4/6 from forming a complex with CyclinD; Arrest proliferation	-	[110]
Palbociclib	HDAC target	entinostat/(MS-275)	Activation of p21 inhibits tumor progression	ER+ breast cancer	[112,113]
Palbociclib	BET inhibitor	JQ1	Prevent proliferation and promote aging	TNBC	[115]
Palbociclib	KDM inhibitor	GSK-J4	Decrease the expression of the E2F target gene and the chromatin accessibility of MYCN	Neuroblastoma	[117]
CDK4/6 inhibitor and other target inhibitors
Palbociclib	lysosome	Antibiotic azithromycin, antidepressant siramesine, antimalaria compound chloroquine	Enhance the synthesis of lysosomes, increase the number of lysosomes, and overcome the drug resistance of CDK4/6 inhibitors	TNBC	[119]
-	PROTAC	-	Degradation of CDK4/6	-	[120,121]
CDK4/6 inhibitor and immunotherapy
Palbociclib/G1T28 (trilaciclib)/Abemaciclib	Immune checkpoint inhibitor	PD-1	Improve immune microenvironment; Enhance anti-tumor immunity; Improve T cell memory; Sensitizing the therapeutic effect of PD-1	Colorectal cancer, ER+ breast cancer	[126,127]