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Page 251 Nickoloff et al. Cancer Drug Resist 2021;4:244-63 I http://dx.doi.org/10.20517/cdr.2020.89

Table 1. DSB repair and DDR targets to enhance radiotherapy
Pathway(s) Target proteins Inhibitors* Ref.
NHEJ DNA-PKcs LY294002, LY3023414, NU7026, NU7441, NU5455, VX-984, CC-115, [150-157]
BCCA621C, IC86621, IC87102, IC87361, OK-1035, SU11752, KU-00600648
EGFR Cetuximab [148,158-160]
HR RAD51 RI-1, B02, CYT-0851, 3E10 (antibody), Fab-F2-iPTD (antibody fragment) [161-166]
BRCA2 BRCA2 siRNA [167]
PARP1 AZD2281, olaparib, veliparib, rucaparib, PJ34, E7016, AG14361, GPI-15427, [168-170]
4-amino-1,8-naphthalimide
DDR ATM, ATR, Chk1/2, Wee1 KU-55933, KU-60019, KU-59403, CP466772, AZD0156, VX-970, VE-821, [34]
AZD-6738, (–)-Schisandrin B, NVP-BEZ235, ETP-46464, AZ-20, AZD-
7762, PF-00477736, XL-844, SCH-900776, prexasertib (LY2606368),
LY2880070, SRA737, GDC-0575, AZD-1775, CJM061
PI3K/AKT/mTOR CC-115, BEZ235, PI103, BKM120, rapamycin, NVP-BEZ235 [156,171-173]
Multiple Hsp90 (DNA-PKcs + 17AAG, PU-871, TAS-116 [174-180]
RAD51)
DNA-PKcs + PARP1 Rucaparib + NU7441, AZD7648 + olaparib, [181,182]
ATM/ATR/Chk1 + PD-L1 shRNA-ATM + PD-L1 antibody [183]
*Inhibitors differ in potency, specificity, and pharmacological properties that determine whether they are restricted to research purposes
or appropriate to advance to pre-clinical and clinical investigations. DDR: DNA damage response; DSB: DNA double-strand break; NHEJ:
non-homologous end-joining; HR: homologous recombination; EGFR: epidermal growth factor receptor

tissues, especially those within the radiation field. In certain solid tumors, such as ovarian and liver cancers,
DNA-PK activity is elevated and this correlates with poor prognoses [185,186] . In these cases, DNA-PKcs
inhibition may improve therapeutic gain. Several small molecule DNA-PKcs inhibitors, and other targeted
approaches, have shown promising results in vitro and in pre-clinical models to enhance radio- and/or
chemotherapy, but few have advanced to human clinical trials, due at least in part to challenges associated
with cross-inhibitory effects against PIKKs (ATM, ATR, and mTOR) or bioavailability.

NU7441 is a fairly specific DNA-PKcs inhibitor that showed promising results as a radiosensitizer against
nasopharyngeal and liver cancer [150,151] , and low concentrations of NU7441 enhance radiosensitivity of
lung cancer cells to both X-rays and carbon ions [152] . Targeting DNA-PKcs with NU7441 in combination
with the PARP1 inhibitor rucaparib radiosensitized Ewing sarcoma cells [181] . The DNA-PKcs inhibitor
VX-984 radiosensitizes glioblastoma cells in vitro and in orthotopic tumors [153] . Two recently developed
small molecule DNA-PKcs inhibitors are NU5455 and AZD7648. NU5455 is a highly selective DNA-PKcs
inhibitor that increases the efficacy of radiotherapy and genotoxic chemotherapy treatment of lung cancer
xenografts [154] . AZD7648 is a highly selective and potent DNA-PKcs inhibitor that enhances radiotherapy of
lung tumor xenografts alone and when combined with the PARP1 inhibitor olaparib; this drug is advancing
to clinical trials [182] . Precise selectivity is not necessarily required: the DNA-PKcs inhibitors, LY3023414
and CC-115, cross-inhibit mTOR (another PIKK) and show promising pre-clinical results. LY3023414 has
advanced to clinical trials [155,156] . In preclinical studies, selective radiosensitization of hypoxic tumors was
achieved using the hypoxia-activated pro-drug BCCA621C to inhibit DNA-PKcs [157] .

Many tumors overexpress wild-type or mutant versions of the epidermal growth factor receptor
(EGFR). The EGFR pathway feeds into the PI3K/AKT/mTOR pathway that drives cell cycle progression.
Interestingly, EGFR pathway activation stimulates DSB repair, and this was traced, at least in part, to an
interaction between AKT1 and DNA-PKcs [187] . In a parallel EGFR pathway, radioresistance of tumor cells
that overexpress Rab5C, Ku70, and Ku80 was traced to Rab5C regulation of EGFR internalization and its
translocation to the nucleus, where EGFR stimulates Ku70/Ku80 expression [188] . Cetuximab, a clinically
useful monoclonal antibody that targets EGFR, inhibits DNA-PKcs [158] and enhanced radiotherapy in early
clinical trials to treat cutaneous squamous cell carcinoma [159] . EGFR nuclear translocation is stimulated
by radiation mediated by Cavelolin-1 (CAV-1), and CAV-1 knockdown radiosensitizes triple-negative
breast cancer, a tumor type for which there are no current targeted therapies and poor prognoses [189] .