The therapeutic utility of
trastuzumab ('
Herceptin') in
breast cancer patients with tumours that overexpress erbB2 established the principle that targeted inhibition of specific signal transduction pathways can provide a new approach to
cancer treatment. The ErbB family of
protein tyrosine kinases, in particular the
epidermal growth factor receptor (EGFR), are commonly overexpressed in many solid human tumours and EGFR was the initial target for a
drug discovery programme seeking small molecule inhibitors of the EGFR
tyrosine kinase (TK)
enzyme activity. The description of the
anilinoquinazoline class of potent and selective TK inhibitors led to several candidate drugs from this chemical class, for example
gefitinib ('
Iressa') and
erlotinib ('
Tarceva'), which are being evaluated in
breast cancer patients. Rapid advances in
cancer molecular genetics have identified numerous potential
drug targets associated with abnormal control of cell division either downstream of the ErbBs, for example Ras and
MEK, or in erbB-associated signalling networks, like
Src kinase, which affect the tumour cell motility and invasiveness. Candidate drugs for several of these targets are currently being evaluated; for example, the prenylation inhibitor
AZD3409, a mimetic of the CAAX box of K-Ras, inhibits
protein farnesyl and geranylgeranyl tranferases and a novel, selective, orally active
Src kinase inhibitor
AZD0530 have entered Phase I clinical trials and may have utility in
breast cancer therapy.