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promoting cell proliferation, but it also interfaces with the DDR, promoting both HR and NHEJ [171] . PI3K/
AKT/mTOR inhibitors sensitize tumor cells to PARP1 inhibitors [224,225] and to radiotherapy [172] . HPV, the
causative agent for most cervical cancers, modulates the DDR to confer therapeutic resistance, and DDR
inhibitors are being explored to improve cervical cancer outcomes [226] . HPV is not alone: many viruses
hijack different parts of the DDR to complete their life cycles [227] . ATM, ATR, and Chk1 signaling modulates
PD-L1 expression in response to DSBs induced by radiation or chemotherapeutics [141] . In preclinical
studies, inhibition of ATM during radiotherapy enhanced tumor immunogenicity and tumor sensitivity to
PD-L1 immune checkpoint blockade [183] . These findings highlight the pleiotropic effects of PIKK signaling
networks and suggest new opportunities for combination therapy to radiosensitize tumors and exploit anti-
tumor activity of the immune system.

SIMULTANEOUS TARGETING OF NHEJ AND HR WITH HSP90 INHIBITORS
Given the importance of DSB repair for cell survival, and the central roles of NHEJ and HR in DSB repair,
simultaneously blocking these pathways can exquisitely sensitize tumors to radio- and chemotherapy.
Hsp90 inhibitors have emerged as important tools for simultaneous downregulation of NHEJ and HR.
Hsp90 is a protein chaperone that regulates stress responses and tumor growth proteins, and Hsp90
inhibitors are being used to treat cancer in monotherapy and to augment traditional therapies [228-230] .
Although Hsp90 is not mutated in tumor cells, it has an altered conformation and higher ATPase activity
than in normal cells. Hsp90 inhibitors exploit this difference to selectively affect tumor cells [174,229,231,232] . The
radiosensitizing effects of Hsp90 inhibitors to low and high LET radiation have been studied for more than
a decade [174-179] . The Hsp90 inhibitor 17-AAG, suppresses HR [176] , radiosensitizes tumor cells, and suppresses
tumor growth after radiotherapy [174] . Interestingly, the greatest radiosensitization was observed with carbon
ions [174] , another example of how HR inhibition potentiates radiosensitization with high LET radiation.
Because protein chaperones affect many cellular processes, Hsp90 inhibitors can have pleiotropic effects,
and early Hsp90 inhibitors caused serious side effects including ocular degeneration [233,234] . Second and third
generation Hsp90 inhibitors (PU-H71 and TAS-116) proved to be safer alternatives. These drugs are tumor-
specific radiosensitizers that suppress both NHEJ and HR by downregulating RAD51, RAD51 foci, and
DNA-PKcs Ser2056/Thr2609 phosphorylation [175,178] . TAS-116 showed promising results in a phase 1 trial
as monotherapy against advanced, heavily pre-treated gastrointestinal and lung cancers, with an acceptable
safety profile (e.g., no greater than grade 1 ocular disorders and nausea) and anti-tumor activity [180] . It will
be interesting to test TAS-116 as an adjunct to radiotherapy, and to carbon ion radiotherapy in particular.

SUMMARY AND FUTURE PERSPECTIVES
DDR signaling, DNA repair, and DNA replication systems are tightly integrated, and they are key regulators
of genome integrity, genome replication, and cell viability/cell proliferative capacity. This means that agents
that target DDR and DNA repair factors can be highly effective against tumors, especially when exploiting
a tumor-specific synthetic lethal weakness. Unfortunately, these systems are also critical in normal cells,
and DDR and DNA repair inhibitors can cause unacceptable normal tissue damage, especially if delivered
systemically, reducing patient quality of life, both short- and long-term, and potentially reducing lifespan
due to organ failure, accelerated tumor progression, or secondary cancers. This delicate balance is
exemplified by a recent study showing that ATM counters toxic NHEJ at collapsed replication forks - an
important finding because it points to new synthetic lethal approaches to treat ATM-defective tumors [235] .
However, it also raises the possibility of ATM inhibition enhancing NHEJ-mediated mis-repair of single-
ended DSBs during (therapy-induced) replication stress. This would destabilize the genome and may
accelerate progression of surviving tumor cells or induce secondary cancers.

Once radio-modulators are proven effective in pre-clinical studies, it is important to determine safe and
effective ways to administer to patients. These will vary depending the type of radio- or chemotherapy