Improving the efficacy of chemoradiation with targeted agents

Abstract

Chemoradiation is the standard therapy for the majority of inoperable, locally advanced cancers. Although there is a need to improve chemoradiation efficacy, normal-tissue toxicity limits our ability to give additional chemotherapy or higher doses of radiation. Thus, there is excitement about the addition of molecularly targeted agents, which tend to be less toxic than chemotherapy, to chemoradiation regimens. Unfortunately, initial empiric attempts have not been successful. This review will focus on the evidence that supports rational combinations of targeted agents with chemoradiation, with an emphasis on agents that target the DNA damage response and radiation-induced membrane signaling.

Figure 1. Variation in Types of DNA Damage and Repair as a Basis for Chemo-Radiosensitization

Each panel schematically represents the status of cell cycle distribution and DNA damage/repair at a time point approximately 12–24 hours post-radiation. Panel A: IR ± Chk1/Wee1 Inhibition. Cells exposed to IR alone (left) contain mostly simple 2-end DSBs that are repaired soon after formation, predominantly by NHEJ in the early part of the cell cycle. A small fraction of damage comprises complex 2-end DSBs and 1-end DSBs, both of which are repaired more slowly and incompletely by NHEJ or HR, as indicated by brown or blue bars, respectively. The intact G2 checkpoint promotes cell survival by delaying progression, allowing slow repair to proceed. Inhibition of Chk1/Wee1 (right) does not change the distribution of the types of damage formed, but compromises repair by preventing HR and by abrogating the G2 checkpoint, resulting in more unrepaired damage (red bars) than with IR only, and in reduced cell survival (sensitization). Panel B: IR+Antimetabolite ± Chk1/Wee1 Inhibition. Antimetabolite treatment prior to IR causes cells to accumulate in S-phase (making them more reliant on HR than NHEJ) and stalls replication forks, increasing the frequency of 1-end DSB formation upon IR treatment. Mis-incorporated nucleotides (dFdCTP or dFdUTP, shown in green) also increase IR-induced complex 2-end DSBs. Intact Chk1/Wee1 function (left) promotes substantial repair through HR and G2 checkpoint stimulation, but the increased burden of breaks that are difficult to repair (especially 1-end DSBs) results in more residual unrepaired damage and cell death than IR alone (sensitization). Inhibition of Chk1/Wee1 (right) causes a large increase in unrepaired damage because of the heavy reliance of the cell on HR and the G2 checkpoint for repair in this situation, and therefore, a high level of sensitization. Panel C: IR+Cisplatin or Temozolomide ± Chk1/Wee1 Inhibition. Drug-induced DNA adducts (shown in yellow) increase the fraction of complex 2-end DSBs. Slower repair kinetics and partial NHEJ inhibition by the presence of adducts leads to increased reliance on HR for repair. With intact Chk1/Wee1 (left), most damage is repaired, although less completely than after IR alone, due to its complexity. Inhibition of Chk1/Wee1 (right) compromises both HR and the G2 checkpoint thus more damage is left unrepaired and there is a concomitant increase in sensitization.

Figure 2. Activated membrane signaling promotes survival in response to radiation

Radiation activates a series of cellular signaling pathways which promote repair of radiation-induced DNA damage as well as other cellular processes (green boxes). Many of these radiation-induced pro-survival pathways can be targeted with small molecule inhibitors or antibodies. Inhibition of these radiation-induced, pro-survival pathways potentially results in maximal potentiation of chemoradiation. EMT, epithelial-to-mesenchymal transition