The abbreviations used in this chapter are listed in at the end of the chapter.

Alternative targets for cancer therapy: towards a scientific rationale

Protein kinases constitute obvious targets for those conditions in which signal transduction pathways have gone awry. In particular, there is much evidence for a decisive role of protein kinases in the development of cancer (see Chapter 11).

By the end of the 1980s, when the search for inhibitors really took off, it was known that the cancer-causing gene (oncogene) of the Rous sarcoma virus encodes a tyrosine protein kinase (v-Src)8 and that one of the genes responsible for cellular transformation by the avian erythroblastosis virus codes for a truncated version of the EGF receptor.9 It was recognized that ErbB2, a member of the EGF receptor family, (also known as Her-2 or neu) is associated with rapid growth and metastasis of human breast cancer.10 In addition, EGF receptors (which are over-expressed in many human tumours11), when transfected into cells at high copy numbers, cause constitutive activation of signal transduction, leading to uncontrolled cell division and development of transformed phenotypes.12–15

Another early line of evidence linking protein kinases with cancer came from chronic myelogenous leukaemia (CML). This is a relatively rare condition in which 95% of patients show a chromosomal abnormality that gives rise

to the expression of a fusion protein Bcr-Abl.16–19. c-Abl was already known to be the precursor, or source, of the v-Abl gene carried by the murine Abelson leukaemia virus.20 The viral oncogene, a fusion product of a cellular Abl and a viral Gag gene, codes for a constitutively activated protein kinase. The fusion protein in CML, just like the viral gene product, is also

a deregulated tyrosine kinase and like v-Abl (160 kDa), Bcr-Abl (210 kD) transforms myeloid cells.21 Mutants that lack the kinase activity are nontransforming. The first unequivocally successful kinase inhibitor to be applied in the treatment of cancer, targets the protein kinase activity of the Bcr-Abl fusion protein.

Phorbol esters such as PMA, well established as tumour promoters, bind and activate protein kinase C (PKC).22 We now recognize that they also bind to many other proteins so the role of PKC in tumour formation remains far from clear (see Chapter 19).

Finally, aberrant proliferation of cells that over-express ErbB2 can be blocked by antibodies raised against that receptor.23 Also, protein kinase inhibitors, competitors of ATP binding, can block growth factor-induced signalling pathways.24–26 Collectively, all these lines of evidence have built a strong rationale from which a handful of successful drugs have since been developed.