Genotypic characteristics of resistant tumors to pre-operative ionizing radiation in rectal cancer

Table 1 Association between DNA-PKcs activity and cancer development from clinical investigations

Tumor type	Assay	Specimen	Sample size	DNA-PKcs activity	Interpretation
Nasopharyngeal cancer	IHC	Tumor	66	↑ in 70% of tumor tissue	No association with locoregional control and survival
Nasopharyngeal cancer	IHC	Tumor	223	↑ in 37% of tumor tissue	Overexpression associated with advanced stage and poor survival
Esophageal cancer	IHC, IB, Kinase activity	Tumor, normal	13 paired	↑ in tumor tissue	NA
Gastric cancer	IHC	Tumor	279	↑ in 73% of tumor tissue	Loss of expression associated with lymphatic invasion, lymph node metastasis, advanced pathological stage, and poor survival
Gastric cancer	IHC	Tumor, normal	791	↑ in 80% of tumor tissue	Loss of expression associated with intratumoral neutrophils, microsatellite instability, mutations in DNA-PKcs and poor survival
Colorectal cancer	RT-PCR, IB, kinase activity	Tumor, normal	12 paired	↑ in tumor tissue	NA
Colorectal cancer	IHC, IB	Tumor, normal	359 (35 paired)	↑ in 64% of tumor tissue	Overexpression associated with clinical stage, lymphatic invasion, distant metastasis and poor survival
Non-small cell lung cancer	IHC	Tumor	113	↑ in 89% of tumor tissue	Overexpression associated with tumor grade
Non-small cell lung cancer	IHC	Tumor	86	↑ in 87% of tumor tissue	No association with clinical characteristics or outcome
Non-small cell lung cancer	RT-PCR	Tumor, normal	140 paired	↑ in tumor tissue	Overexpression associated with poor survival
Non-small cell lung cancer	IHC	Tumor, normal	116 (12 paired)	↑ in 75% of tumor tissue	No association with clinical characteristics or outcome
Glioma	Kinase activity	Tumor	36	↑ in tumor tissue	Hyperactivity correlates with rumor grading
Ovarian cancer	IHC	Tumor, normal	100	↓ in 40% of tumor tissue	loss of expression associated with tumor progression, advanced clincal stage, and lymph node metastasis
ALL, CLL, lymphoma, multiple myeloma	IHC, IB	Lymphoid tissue	86	↑ During lymphoid development and in lymphoid malignancies	Overexpression associated with higher lymphoma grading and degree of maturation in lymphoid malignancies other than multiple myeloma
B-cell CLL	IB, kinase activity	Lukemia cells	54	↑ in del(17p) and del(11q)	Overexpression associated with shorter treatment free interval
B-cell CLL	RT-PCR	Lukemia cells	50	↑ in del(17p)	Overexpression associated with poor survival
Cancer of breast, cervix, head and neck esophageal and lymphoma	Kinase activity	PBLs	167	↓ in advanced stage	Hypoactivity associated with advanced stage and distant metastasis
Radiation response
Esophageal cancer	IHC	Tumor	67	↑ in 54% of tumor tissue	Overexpression predicts better response to chemoradiation
Oral squamous cell carcinoma	IHC	Tumor	42	↑ in residual tumor after RT	Not predictive of radiation response
Cervical cancer	IHC	Tumor	22	↑ in residual tumor after RT	No association with clinical characteristics
Breast cancer	IHC	Tumor	224	↑ in 43% of tumor tissue	Overexpression predicts better locoregional control of radiation alone versus chemotherapy alone in early stage
Cancer risk
Lung cancer	Kinase activity	PBLs	Cancer 41/healthy 41	↓ in cancer patients	Hypoactivity associated with cancer of the lung
Breast, cervix, head and neck, esophagus and lymphoma	Kinase activity	PBLs	Cancer 93/healthy 41	↓ in cancer patients	Hypoactivity associated with chromosomal instability and cancer of breast and cervix

Adapted with permission[148]. ALL: Acute lymphocytic leukemia; CLL: Chronic lymphocytic leukemia; IHC: Immunohistochemistry; PBLs: Peripheral blood lymphocytes; RT-PCR: Reverse transcription polymerase chain reaction; ↑: Indicates increase activity; ↓: Indicates decrease activity.

Table 2 Non-homologous end-joining inhibitors

Inhibitor	Mechanism/comments
A12B4C3	PNKP inhibitor, sensitizes cells to camptothecin
BTW3	A small peptide DNA-PK inhibitor, proposed to compete for DNA-PKcs autophosphorylation
KU0060648	DNA-PK and P13K inhibitor
NU7441/KU57788	DNA-PK inhibitor, competitive with ATP
ScFv 18-2	An antibody-derived DNA-PK inhibitor that can bind to an epitope unique to DNA-PKcs
ZSTK474	DNA-PK and P13K inhibitor, competitive with ATP; in phase 1 clinical trials (NCT01280487 and NCT01682473)
CC-115	Dual inhibitor of DNA-PKcs and mTOR, in phase 1 clinical trials
CC-122	DNA-PK inhibitor, in phase 1 clinical trials

Reprinted with permission from Elsevier[149]. P13K: Phosphatidyl inositol 3 kinase.