DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Abstract

DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.

Keywords: DDR modulators; DNA damage response; DNA damage-inducing therapies; DNA repair; cancer therapy; combination therapies; cytotoxic chemotherapy; radiotherapy.

Figure 1

Overview of the DNA damage response. (A) General overview of the DDR signaling cascade upon DNA damage induction, either endogenously or by external agents. After damage detection by sensor proteins, transducer proteins activate effector proteins that can elicit a variety of cellular responses. Cell cycle checkpoints will be activated to halt proliferation and allow time for (accurate) repair. However, the inability to repair the induced damage can also lead to induction of detrimental cellular fates such as apoptosis. (B) Visualization of types of DNA damage that can be induced, as well as the main pathways that are directly involved in their repair. Abbreviations: SSB: single-strand break; DSB: double-strand break; FA pathway: Fanconi anemia pathway.

Figure 2

Overview of DNA damage induction patterns as a function of tissue depth for two types of EBRT, using either photon or proton beams. The induction of damage in superficial and deeper tissues is visualized (upper panel), as well as the course of the relative dose with increasing tissue depth (lower panel). (A) For photon beams, the highest dose will be deposited at the body entrance site, corresponding with the highest density of induced DNA lesions. The local relative dose will then decrease with increasing penetration depth in tissues. (B) For proton beams, the entrance dose is relatively low, followed by a sharp peak (the Bragg peak) in deeper tissues. Correspondingly, induced DNA damage will be most significant in these deeper tissues.

Figure 3

Visualization of DNA damage induction patterns of beta-emitters, alpha-emitters and Auger electrons, ordered (from left to right) by decreasing penetration range and increasing complexity of induced DNA damage. While beta-emitters exhibit a relatively long penetration range, they mostly induce isolated lesions. Alpha-emitters have a shorter range, but can locally induce more complex forms of DNA damage that are less readily repaired. Auger electrons display the shortest range of the three, but due to the fact that multiple electrons are released from the radionuclide they can still induce a high biological effect locally.

Figure 4

Visualization of the DNA-targeted mechanisms of action of radiotherapy, cytotoxic chemotherapy and DDR modulators. 1. Ionizing radiation (IR) can induce DNA damage both directly and indirectly (through ROS formation), leading to formation of SSBs, DSBs and different base lesions. Depending on the radiation type used, clustered (complex) DNA damage might be induced when multiple DNA lesions are formed in close vicinity. 2. Alkylating and platinum-based compounds harbor a reactive site and directly react with the DNA molecule., forming DNA adducts and intra- or interstrand crosslinks. 3. Antimetabolites mimic molecules essential in DNA replication and repair and, depending on the specific compound, can be incorporated in the DNA leading to DNA damage. Alternatively. antimetabolites can inhibit nucleotide producing pathways. 4. TOPI- and TOPII-poisons, the most clinically relevant topoisomerase inhibitors, trap topoisomerases on the DNA, preventing re-ligation of topoisomerase-induced breaks. For TOP1 poisons, DSBs are formed when DNA polymerase stalls on this trapped complex. However, for TOPII-poisons, trapping leads to the persistence of topoisomerase-induced DSBs. 5. Antitumor antibiotics can have different DNA-targeted mechanisms of action, such as compound intercalation in the DNA and induction of ROS formation. Other antitumor antibiotic mechanisms of action overlap with other cytotoxic chemotherapeutic classes, such as DNA alkylation and topoisomerase poisoning. 6. DDR modulators target specific DDR proteins and exert their cancer-inhibiting effect by synthetic lethality: as cancer cells that have loss-of-function mutations in specific DDR pathways become more reliant on backup repair pathways, inhibition of the latter by DDR modulators can specifically target cancer cells versus healthy cells.