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Figure 3. Repair and mis-repair of one-ended DSBs at collapsed replication forks. Single-strand breaks (SSB) and single-strand DNA
lesions may be repaired prior to replication. If encountered by a replication fork, SSBs and single-strand lesions cause fork collapse and
fork stalling, respectively. Stalled forks may collapse when cleaved by MUS81 or EEPD1. Collapsed forks create one-ended DSBs that
can initiate fork restart by HR, or they may be joined to other DSB ends (at collapsed forks or frank DSBs) by NHEJ or alt-NHEJ, creating
large-scale genome rearrangements. DSBs: DNA double-strand breaks; HR: homologous recombination; NHEJ: non-homologous end-
joining

from PARP1-trapping on damaged DNA, accounting for the synthetic lethality of PARP1 inhibitors in HR-
deficient tumor cells [35,208] . PARP1 inhibitors are widely used in clinical management of HR-defective breast
and ovarian cancers [209,210] and are being explored as adjuncts to radiotherapy [168-170] . To inhibit proteins such
as BRCA2 for which there are no small molecule inhibitors, genetic approaches such as siRNA knockdown
offer another means to transiently induce HR defects to enhance radiosensitivity [167] . HR defects, whether
intrinsic to the tumor or induced by drugs or other means, may be particularly useful when paired with
high LET carbon ions given the greater importance of HR in repair of clustered DSBs [64,76-78,167] . Just as HR
defects sensitize cells to radiation and genotoxic chemotherapy, therapeutic resistance to these agents, and
to PARP1 inhibitors, correlates with restoration or upregulation of HR [211-215] . Radiosensitization of tumors
with HR inhibitors may thus be most effective against cancers that upregulate HR.

TARGETING DDR SIGNALING FACTORS
The DDR is important for tumor suppression, and it also comprises important targets that mediate
therapeutic resistance to radiation and chemotherapy [216] . ATM and ATR are key regulators of critical HR
factors, including MRE11, NBS1, CtIP, p53, RPA, BRCA1, PALB2, H2AX, and RAD51 [37,192,217,218] . ATM,
[30]
ATR, and DNA-PKcs collaborate to regulate HR, NHEJ, and DNA damage checkpoint responses .
Targeting these PIKKs and other DDR factors, including Chk1, Chk2, and Wee1, are very active research
topics [35,97,146,148,149,219] . Some DDR inhibitors show significant toxicity, hence delivery during protracted,
fractionated radiotherapy raises safety concerns; these might be mitigated by using localized drug delivery.
Nonetheless, several DDR inhibitors have advanced to clinical trials, including two phase 1 trials to
augment radiotherapy with the ATR inhibitors VX-970 and AZD6738 [34,220] . ATM inhibitors, including
AZD1390 and AZD0156, have shown promise for radiosensitizing various solid tumors in preclinical
studies, including glioblastoma, head and neck cancer, and lung cancer [34,221-223] . ATM and ATR inhibitors
are also being tested for synthetic lethal effects with PARP1 inhibitors [220-222] ; such combinations may also
augment radiotherapy. The PI3K/AKT/mTOR pathway has well-defined roles in suppressing apoptosis and