Figure 20–42 The conversion of the Abl proto-oncogene into an oncogene in patients with chronic myelogenous leukemia. The chromosome translocation responsible joins the Bcr gene on chromosome 22 to the Abl gene from chromosome 9, thereby generating a Philadelphia chromosome (see Figure 20–5). The resulting fusion protein has the N-terminus of the Bcr protein joined to the C-terminus of the Abl tyrosine protein kinase; in consequence, the Abl kinase domain becomes inappropriately active, driving excessive proliferation of a clone of hemopoietic cells in the bone marrow.
Figure 20–43 How imatinib (Gleevec) blocks the activity of Bcr-Abl protein and halts chronic myelogenous leukemia.
(A) Imatinib sits in the ATP-binding pocket of the tyrosine kinase domain of Bcr-Abl and thereby prevents Bcr-Abl from transferring a phosphate group from ATP onto a tyrosine residue in a substrate protein. This blocks transmission of a signal for cell proliferation and survival. (B) The structure of the complex of imatinib (solid blue object) with the tyrosine kinase domain of the Abl protein (ribbon diagram), as determined by x-ray crystallography. (C) The chemical structure of the drug. It can be given by mouth; it has side effects, but they are usually quite tolerable. (B, from T. Schindler et al., Science 289:1938–1942, 2000. With permission from AAAS.)
Results are not so good for those patients who have already progressed to the more acute phase of myeloid leukemia, known as blast crisis, where genetic instability has set in and the march of the disease is far more rapid. These patients show a response at first and then relapse because the cancer cells develop a resistance to imatinib. This resistance is usually associated with secondary mutations in the part of the Bcr-Abl gene that encodes the kinase domain, disrupting the ability of imatinib to bind to Bcr-Abl kinase. Second-generation inhibitors that function effectively against a whole range of imatinib-resistant mutants have now been developed. By combining one or more of these new inhibitors with imatinib as the initial therapy (see below), it seems that CML—at least in the chronic (early) stage—may be on its way to becoming a curable disease.
Despite the complications with resistance, the extraordinary success of imatinib is enough to drive home an important principle: once we understand precisely what genetic lesions have occurred in a cancer, we can begin to design effective rational methods to treat it. This success story has fueled efforts to identify small-molecule inhibitors for other oncogenic protein kinases and to use them to attack the appropriate cancer cells. Increasing numbers are being developed. These include molecules that target the EGF receptor and are currently approved for the treatment of some lung cancers, as well as drugs that specifically target the B-Raf oncoprotein in melanomas.
Protein kinases have been relatively easy to inhibit with small molecules like imatinib, and many kinase inhibitors are being produced by pharmaceutical companies in the hope that they can be effective as drugs for some forms of cancer. Many cancers lack an oncogenic mutation in a protein kinase. But most tumors contain inappropriately activated signaling pathways, for which a target somewhere in the pathway can hopefully be found (Movie 20.7). As an example, Figure 20–44 displays some of the anticancer drugs and drug targets that are currently being tested for a pathway frequently activated in cancers.
Many Cancers May Be Treatable by Enhancing the Immune Response Against the Specific Tumor
Cancers have complex interactions with the immune system, and its various components may sometimes help as well as hinder tumor progression. But for more than a century it has been a dream of cancer researchers to somehow harness the immune system in a controlled and efficient way to exterminate cancer cells, just as it exterminates infectious organisms. There are finally signs that this dream may one day be realized, at least for some forms of cancer.