Table 1.

Incidence of senescence in cancer and premalignancy. 5‐FU, 5‐fluorouracil; γH2AX, phosphorylation of the Ser‐139 residue of the histone variant H2AX; CCL2, C–C‐motif chemokine ligand 2; CDK1, cyclin‐dependent kinase 1; EGFR, epidermal growth factor receptor; ELISA, enzyme‐linked immunosorbent assay; GRO‐alpha/CXCL1, chemokine (C‐X‐C‐motif) ligand 1; HER, human epidermal growth factor receptor; IGFBP‐2, insulin‐like growth factor binding protein 2; IF, immunofluorescence; IHC, immunohistochemistry; IL, interleukin; IR, ionising radiation; NF1, neurofibromin; NSCLC, non‐smallcell lung carcinoma; p53BP1, p53‐binding protein 1; PAI‐1, plasminogen activator inhibitor‐1; PDX, patient‐derived xenografts; Pten, phosphatase and tensin homolog; Rb1, retinoblastoma protein 1; Rheb, Ras homolog enriched in brain; Stat3, signal transducer and activator of transcription 3; TKI, tyrosine kinase inhibitor; VEFGA, vascular endothelial growth factor A.

Gene	Tumour or premalignancy	Mechanism	Reference
Mouse models of oncogene‐induced senescence
HrasG12V	Breast tumour, bladder tumour, skin papilloma and angiosarcoma	Oncogene activation	[258, 259, 260, 261, 262]
KrasG12V	Lung adenoma and pancreatic intraductal neoplasia	Oncogene activation	[122]
KrasG12D	Lung adenoma	Oncogene activation	[263]
NrasG12D	Lymphoproliferative disorder	Oncogene activation	[85]
BrafV600E	Nevi, lung adenoma and melanoma	Oncogene activation	[121, 126, 264, 265]
Rheb	Prostate intraepithelial neoplasia	Oncogene activation	[266]
E2f3	Pituitary hyperplasia	Oncogene activation	[123]
Akt1	Prostate intraepithelial neoplasia	Oncogene activation	[267]
Myc	Lymphoma, osteosarcoma, liver and lung carcinoma	Oncogene inactivation	[142, 268]
Trp53	Sarcoma and liver carcinoma	Tumour suppressor activation	[141, 269]
Pten	Prostate intraepithelial neoplasia	Tumour suppressor inactivation	[87, 270]
Rb1	Thyroid C cell adenoma	Tumour suppressor inactivation	[271]
Stat3	Breast tumour	Tumour suppressor inactivation	[272]
Human tissues with oncogene‐induced senescence
BRAFV600E	Papillary thyroid carcinomas and nevi	Oncogene activation	[125, 126]
NF1	Dermal neurofibromas	Tumour suppressor inactivation	[127]

Therapeutic agent	Tumour or malignancy	Mechanism	Reference
Therapy‐induced senescence with irradiation (IR) or drugs
5‐aza‐2′‐deoxycytidine (Dacogen)	Colorectal tumour, renal cell carcinoma, hepatoma and NSCLC	Inhibition of DNA methyltransferase	[273]
5‐aza‐cytidine (Decitabine)	Malignant pleural mesothelioma	Inhibition of DNA methyltransferase	[274]
Axitinib (Inlyta®)	Glioblastoma	TKI	[275]
BRD4770	Pancreatic adenocarcinoma	Inhibition of histone methyltransferase	[276]
Doxorubicin	MMTV‐Wnt1 mice with mammary tumour	DNA damage (DNA intercalator)	[140]
Erlotinib and IR	NSCLC Xenografts of A549 NSCLC	DNA damage and TKI	[129]
Imidazoacridinone C‐1311 (Symadex™)	Colorectal tumour, NSCLC and oesophageal carcinoma	DNA damage (inhibition of topoisomerase II)	[277]
IR	Lung adenoma, breast tumour, colorectal tumour, glioblastoma and neuroblastoma Xenografts of H460 lung carcinoma	DNA damage	[130, 278, 279, 280]
Lapatinib	Breast tumour	HER2‐targeted TKI	[135]
LBH589 (Panobinostat)	Osteosarcoma Xenografts of osteosarcoma	Inhibition of histone deacetylase	[281]
MLN4924	Colorectal tumour, NSCLC, glioblastoma, lymphoma, gastric tumour and osteosarcoma Xenografts of SJSA‐1 osteosarcoma	DNA damage (inhibition of NEDD8 activating enzyme)	[282, 283, 284, 285]
MLN8054	Colorectal tumour and NSCLC Xenografts of HCT116 colorectal tumour	Inhibition of Aurora A kinase	[286]
Neratinib and afatinib	Breast tumour	panHER TKI	[135]
Palbociclib	Patient‐derived sarcoma cells PDX of sarcoma	Inhibition of CDK4/6	[287]
Palbociclib	Melanoma Xenografts of 983B/983BR melanoma	Inhibition of CDK4/6	[288]
Palbociclib and chloroquine or hydroxychloroquine	Breast tumour Xenografts of MCF7‐T breast tumour	Inhibition of CDK4/6 and autophagy	[289]
Ribociclib	Neuroblastoma Xenografts of BE2C, 1643 and EBC1 neuroblastoma	Inhibition of CDK4/6	[290]
Sunitinib (SU11248)	Renal cell carcinoma Xenografts of OS‐RC‐2 renal cell carcinoma	TKI	[137]
Vemurafenib (PLX4032)	Melanoma Xenografts of SK‐MEL‐28 melanoma	Inhibition of BRAF	[291]
VO‐OHpic	MEF and prostate cancer Xenografts of MDA PCa‐2b prostate cancer	Inhibition of PTEN	[292]
WM‐1119	MEF Xenografts of EMRK1184 lymphoma	Inhibition of histone acetyltransferases	[136]
WM‐8014	MEF Zebrafish model of hepatocarcinoma	Inhibition of histone acetyltransferases	[136]

Therapeutic regimens	Malignancy	Evidence of senescence	Reference
Human tissues with therapy‐induced senescence
Neoadjuvant chemotherapy containing cyclophosphamide, doxorubicin, and 5‐FU	Breast cancer	SAβG and IHC of p53 and p21WAF1/CIP1	[293]
Neoadjuvant chemotherapy containing carboplatin and docetaxel	NSCLC	SAβG and IHC of CDK1	[185]
Neoadjuvant chemotherapy containing cisplatin and gemcitabine or pemetrexed	Malignant pleural mesothelioma	SAβG and IHC of PAI‐1 and p21WAF1/CIP1	[294]
Neoadjuvant chemotherapy containing mitoxantrone	Prostate cancer	qPCR of p16INK4a , p21WAF1/CIP1 and SASP factors including IL‐6, IL‐8, GRO‐alpha/CXCL1, IGFBP‐2, and IL‐1beta	[167]
Neoadjuvant chemotherapy containing sunitinib (SU11248)	Renal cell carcinoma	SAβG and IHC of p53, Dec1, and Ki67	[137]
Neoadjuvant or adjuvant chemotherapy containing anthracycline	Breast cancer	qPCR of p16INK4a and ARF; ELISA of SASP factor VEGFA and CCL2 (assessed using peripheral blood T lymphocytes and patient sera)	[139]
Radiotherapy	Head and neck cancer	IF of γH2AX and p53BP1; IHC of p21WAF1/CIP1 (assessed using patient salivary gland)	[177]
Neoadjuvant chemoradiotherapy containing 5‐FU	Rectal cancer	qPCR of p21WAF1/CIP1 , p16INK4a and IL‐8	[138]