Cancer treatment with kinase inhibitors: what have we learnt from imatinib?

Abstract

Over the past few years, a number of anticancer drugs have been developed that specifically target kinases known to be oncogenic. The leading drug in this area is imatinib mesylate, which targets ABL, KIT and PDGFR. It has been remarkably effective in the treatment of chronic myeloid leukaemia, although resistance remains a significant problem. From the imatinib experience in this setting, we present some principles of kinase inhibition that may have more general applicability in targeted anticancer therapy. It is clear that the identification of appropriate targets (activated kinases) and monitoring levels of response (to recognise emerging resistance) are essential to optimise clinical management.

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy

“…For patients with newly diagnosed CML, the optimal dose of imatinib and the best approach for management of patients with suboptimal disease response are not known. [16][17][18][41][42][43][44] Promising results with higher doses of imatinib have raised questions about whether the dosing schedule of 400 mg/day selected for the IRIS study is the best approach. In addition, the IRIS trial did not allow dose escalation unless patients failed to achieve an MCR by 12 months or lost MCR.…”

Malignant Gastrointestinal Stromal Tumor of the Small Intestine Complicated with Pulmonary Tuberculosis during Treatment with Imatinib Mesylate

“…Until the year 2000, the prognosis for patients with metastatic GISTs was very poor, but the advent of imatinib mesylate (formerly STI571, [Glivec]; Novartis, Basel, Switzerland) has dramatically changed this perception (5)(6)(7). By analogy to its inhibitory effect on the BCR-ABL tyrosine kinase in CML, it was postulated that imatinib mesylate would selectively inhibit the constitutive activity of c-kit proto-oncogene which encodes the receptor (KIT) tyrosine kinase in GISTs (8)(9)(10)(11). Here, we report a case of malignant GIST of the small intestine complicated with pulmonary tuberculosis during treatment with imatinib mesylate.…”

Multistage carcinogenesis

“…Gleevec (imatinib) acts on the oncoprotein created by a specific chromosome re-arrangement in chronic myelocytic leukaemia (Ross and Hughes, 2004), something that would surely delight Boveri were he alive today. Inhibitors of tyrosine kinase receptors and their downstream signalling pathways present promising targets for translating our scientific understanding of *Correspondence: RA Weiss; E-mail: r.weiss@ucl.ac.uk (Ranson, 2004;Ross and Hughes, 2004). Translational and clinical research of this kind is specially welcomed by BJC, as well as investigations in molecular diagnostics, cancer genetics and epidemiology.…”