Table 2.

a Overview of the dysregulated expression and functions of the major cell cycle proteins contribute to the intrinsic resistance to CDK4/6 inhibitors. b Overview of other mitogenic signaling activation to CDK4/6 inhibition and combination strategies.

Gene	Expression	Cancer type	Functions	References
RB1	Rb1 loss	Breast cancer	Resistance to palbociclib	[9]
RB1	Rb1 loss	Ovarian cancer	Resistance to palbociclib	[15]
RB1	Rb1degradation	HPV-positive cervical cancer and head and neck cancer	Resistance to CDK4/6 inhibitors	[16, 17]
CDK4	CDK4-amplification	Liposarcoma and Neuroblastoma	Sensitive to CDK4/6 inhibitors	[26, 27]
CDK4	Activation T172 phosphorylation	Breast cancer	Enhance the sensitivity to palbociclib	[28]
CDK4	CDK4-amplification	Rhabdomyosarcoma	Reduce the sensitivity to ribociclib	[25]
CCND1	Cyclin D1-overexpression	Endometrial cancer	Enhance the sensitivity to abemaciclib	[32]
SMARCA4	SMARCA4 loss	Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cells	Cause cyclin D1 deficiency and enhance the sensitivity to CDK4/6 inhibitors	[33]
]SMARCA2/4	SMARCA2/4 loss	Non-small cancer cell	Cause cyclin D1 deficiency and increase the sensitivity to CDK4/6 inhibitors	[34]
CDKN2A	p16INK4A loss	Melanoma	Good for palbociclib sensitivity	[40]
CDKN2A	p16INK4A loss	Pancreatic ductal adenocarcinoma	Resistance to CDK4/6 inhibitors	[41]
CDKN2A	p16INK4A deficiency	Glioblastoma	More susceptible to palbociclib	[42]
CCNE1	Cyclin E1 overexpression	Gastric cancer	Resistance to palbociclib	[37]
CCNE1	High cyclin E1 expression	HR+ HER2- breast cancer	Resistance to palbociclib	[38]
E2F4	E2F4 activation	ER+ breast cancer	Resistance to palbociclib	[21]
E2F	E2F activation	Mutant BRAF and NRAS melanoma	Resistance to palbociclib	[22]
TP53	p53 loss	Breast cancer	Resistance to abemaciclib	[45]
CDK2	High levels of CDK2 activity	Luminal androgen receptor breast cancer	Resistance to CDK4/6 inhibitors	[31]

Other mitogenic signaling	Cancer type	Functions	Combination with other inhibitors	References
FGFR1 amplification	ER+ breast cancer	Resistance to CDK4/6 inhibitors	Lucitanib (FGFR inhibitors)	[54]
FGFR1 signaling pathway activation	KRAS-mutant non-small lung cancer	Resistance to CDK4/6 inhibitors	MEK inhibitors	[55]
MAPK signaling pathway activation	prostate cancer	Resistance to CDK4/6 inhibitors	MEK inhibitors	[56]
PIK3CA E545K mutation	NRAS-mutant melanoma	Resistance to CDK4/6 inhibitors	mTOR inhibitors and S6K1 inhibitors	[57]
mTOR activation	Pancreatic cancer	Resistance to CDK4/6 inhibitors	mTOR inhibitors	[60]
PDK1 activation	ER+  breast cancer	Resistance to ribociclib	PDK1 inhibitors or CDK2 inhibitors	[61]
NF-κB-HGF pathway	Glioblastoma	Resistance to ribociclib	Altiratinib (c-Met/Trk inhibitor)	[62]
Androgen Receptor activation	Breast cancer	Resistance to palbociclib	Androgen receptor inhibitors	[63]
FAT1 loss (Hippo pathway suppression)	ER+ breast cancer	CDK6 overexpression		[64, 65]
MYC-driven (mTOR activation)	Colorectal carcinoma	Resistance to CDK4/6 inhibitors		[66]
Fbxo4 loss (Gln-addition)	Esophageal squamous cell carcinoma	Resistance to CDK4/6 inhibitors	Glutaminase1plus metformin or phenformin	[67]
IL6/STAT3 activation	ER+ breast cancer	Resistance to CDK4/6 inhibitors	STAT3 inhibitor plus PARP inhibitor	[68]