PARP Inhibitors: The Journey From Research Hypothesis to Clinical Approval

Kishan AT Naipal; Dik C van Gent


Personalized Medicine. 2015;12(2):139-154. 

In This Article

Genetic Concepts for Targeted Cancer Treatment

The most common rationale for targeted treatment is oncogene addiction, which was postulated already a decade ago.[4,5] It covers all cases where cancer cells become dependent on the prolonged activity of activated oncogenes resulting in a selective growth advantage (Figure 1A). Targeting this specific 'addiction' causes tumor cell specific toxicity. One famous example of targeting oncogene addiction is the treatment of chronic myeloid leukemia (CML) caused by the fused oncogene BCR/ABL with the selective ATP-binding inhibitor Imatinib.[6] This approach greatly improved patient outcome by its selective potent activity and relatively mild toxicity. The concept of targeting oncogene addiction has been used in other tumor types as well, for example, Tamoxifen and Herceptin treatment in estrogen receptor positive and HER2-positive breast cancers, respectively,[7,8] and specific BRAF inhibitor treatment in BRAF V600 mutated melanomas.[9,10]

Figure 1.

Genetic concepts in targeted cancer treatment. (A) Oncogene addiction in case the viability/proliferative capacity of a tumor cell depends mainly on one hyper activated oncogene (blue box). Selectively targeting this activated oncogene will result in tumor cell death. Normal cells will have minimal effect of the intervention as proliferation does not solemnly depends on that specific oncogene. (B) Synthetic lethality, a situation where cell viability depends on two genes, mostly tumor suppressor genes. Inhibiting one gene will not effect cell viability however, inhibiting both genes will induce cell death. In this example a defect in gene A is synthetically lethal with a defect in gene B.
For color images see online

Another important concept in targeted treatment is synthetic lethality. This term originated from work performed with yeast and fruitflies and was proposed for therapeutic interventions by Hartwell et al..[11,12] It includes a situation where a defect in one gene, gene A, causes dependency or induced essentiality of another gene, gene B, for cellular survival (Figure 1B). Targeting of gene B in this case is synthetically lethal in combination with a defect in gene A and results in cell death. Targeting gene B without a defect in gene A will have minimal effect on cell survival. Following Hartwell et al., many investigators have tried to identify synthetically lethal combinations of genes that are frequently associated with cancer. All these synthetic lethal approaches are expected to achieve tumor-specific cell killing with minimal side-effects. Treatment of BRCA1/2 defective tumors with Poly-(ADP-Ribose)-polymerase (PARP) inhibitors is a well advanced example of such a combination, simultaneously reported in 2005 by two different research groups.[13,14]