Figure 20–41 How a tumor’s genetic instability can be exploited for cancer therapy. As explained in Chapter 5, the maintenance of DNA sequences is so critical for life that cells have evolved multiple pathways for repairing DNA damage and reducing DNA replication errors. As illustrated, a DNA replication fork will stall whenever it encounters a break in a DNA template strand. In this example, normal cells have two different repair pathways that help them to avoid the problem, pathways 1 and 2. They are therefore not harmed by treatment with a drug that blocks repair pathway 1. But, because the inactivation of repair pathway 2 was selected for during the evolution of the tumor cell, the tumor cells are killed by the same drug treatment.
In the actual case that underlies this example, the function of repair pathway 1 (requiring the PARP protein discussed in the text) is to remove persistent, accidental breaks in a DNA single strand before they are encountered by a moving replication fork. Pathway 2 is the recombination-dependent process (requiring the Brca2 and Brca1 proteins) for repairing stalled replication forks illustrated in Figure 5–50. PARP inhibitors have promise for treating cancers with defective Brca2 or Brca1 tumor suppressor genes.
PARP inhibition provides an example of the type of rational, highly selective approach to cancer therapy that is beginning to be possible. Along with other new treatments to be discussed below, it raises high hopes for treating many other cancers.
Small Molecules Can Be Designed to Inhibit Specific Oncogenic Proteins
An obvious tactic for treating cancer is to attack a tumor expressing an oncogene with a drug designed to specifically block the function of the protein that the oncogene produces. But how can such a treatment avoid hurting the normal cells that depend on the function of the proto-oncogene from which the oncogene has evolved, and why should the drug kill the cancer cells, rather than simply calm them down? One answer may lie in the phenomenon of oncogene dependence. Once a cancer cell has undergone an oncogenic mutation, it will often undergo further mutations, epigenetic changes, or physiological adaptations that make it reliant on the hyperactivity of the initial oncogene, just as drug addicts become reliant on high doses of their drug. Blocking the activity of the oncogenic protein may then kill the cancer cell without significantly harming its normal neighbors. Some remarkable successes have been achieved in this way.
As we saw earlier, chronic myelogenous leukemia (CML) is usually associated with a particular chromosomal translocation, visible as the Philadelphia chromosome (see Figure 20–5). This results from chromosome breakage and rejoining at the sites of two specific genes, Abl and Bcr. The fusion of these genes creates a hybrid gene, called Bcr-Abl, that codes for a chimeric protein consisting of the N-terminal fragment of Bcr fused to the C-terminal portion of Abl (Figure 20–42). Abl is a tyrosine kinase involved in cell signaling. The substitution of the Bcr fragment for the normal N-terminus of Abl makes it hyperactive, so that it stimulates inappropriate proliferation of the hemopoietic precursor cells that contain it and prevents these cells from dying by apoptosis—which many of them would normally do. As a result, excessive numbers of white blood cells accumulate in the bloodstream, producing CML.
The chimeric Bcr-Abl protein is an obvious target for therapeutic attack. Searches for synthetic drug molecules that can inhibit the activity of tyrosine kinases discovered one, called imatinib (trade name Gleevec®), that blocks Bcr-Abl (Figure 20–43). When the drug was first given to patients with CML, nearly all of them showed a dramatic response, with an apparent disappearance of the cells carrying the Philadelphia chromosome in over 80% of patients. The response appears relatively durable: after years of continuous treatment, many patients have not progressed to later stages of the disease—although imatinib-resistant cancers emerge with a probability of about 5% per year during the early years.