William L. Elliott

CI-1033, a pan-erbB tyrosine kinase inhibitor

Overexpression of the erbB family of receptor tyrosine kinases has been implicated in a variety of tumors including breast, lung, prostate, and brain. Most solid tumors express one or more of these receptors, which can often be related to tumor aggressiveness and poor patient prognosis. CI-1033, a pan-erbB tyrosine kinase inhibitor, is a clinically promising agent that is active against all four members of the erbB receptor tyrosine kinase family. In vitro studies of human cancer cell lines indicate that CI-1033 results in prompt, potent, and sustained inhibition of tyrosine kinase activity. This inhibition is highly selective for erbB1 (epidermal growth factor receptor), erbB2, erbB3, and erbB4 without inhibiting tyrosine kinase activity of receptors such as platelet-derived growth factor receptor, fibroblast growth factor receptor, and insulin receptor, even at high concentrations. Treatment of athymic nude mice bearing xenografts of human A431 epidermoid carcinoma, H125 non-small cell lung carcinoma, and SF-767 glioblastoma results in highly significant suppression of tumor growth. The major toxicity in animals is diarrhea, which is more severe at higher doses. In animal models, all side effects are reversible on cessation of treatment. Thus, CI-1033, which is currently undergoing phase I clinical trials, holds significant potential for use in a broad range of solid tumors.

Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer.

Transmembrane receptor tyrosine kinases have been shown to play an important role in the modulation of growth factor signaling and regulation of key cellular processes. The erbB receptor family is part of the receptor tyrosine kinase superfamily and consists of four members, erbB-1, erbB-2, erbB-3, and erbB-4. A majority of solid tumors express one or more members of this receptor family, and coexpression of multiple erbB receptors leads to an enhanced transforming potential and worsened prognosis. The erbB receptor family has been shown to play an important role in both the development of the normal breast and in the pathogenesis and progression of breast cancer. Receptor overexpression has also been shown to be a negative prognostic indicator and to correlate with both tumor invasiveness and a lack of responsiveness to standard treatment. Clinically, blockade of the erbB-2 receptor has recently been shown to provide benefit in a subset of chemotherapy-resistant breast cancer patients. CI-1033 is an orally available pan-erbB receptor tyrosine kinase inhibitor that, unlike the majority of receptor inhibitors, effectively blocks signal transduction through all four members of the erbB family. In addition, it blocks the highly tumorigenic, constitutively activated variant of erbB-1, EGFRvIII, and inhibits downstream signaling through both the Ras/MAP kinase, and PI-3 kinase/AKT pathways. CI-1033 is also unique in that it is an irreversible inhibitor, thereby providing prolonged suppression of erbB receptor-mediated signaling. Preclinical data have shown CI-1033 to be efficacious against a variety of human tumors in mouse xenograft models, including breast carcinomas. In a phase I study, CI-1033 has been shown to have an acceptable side effect profile at potentially therapeutic dose levels and demonstrates evidence of target biomarker modulation. Antitumor activity has also been observed in this study, including one partial clinical response and stable disease in over 30% of patients, including one patient with heavily pretreated breast cancer. By virtue of its pan-erbB receptor inhibition and potent interruption of downstream mitogenic signaling pathways, CI-1033 may have clinical activity for solid tumors that overexpress one erbB family member, coexpress multiple members of the erbB family, or express a constitutively activated, mutated form of these receptors. Given the important role of the erbB receptor family in the pathogenesis and progression of breast cancer, an irreversible pan-erbB inhibitor like CI-1033 could have an important role to play in the future treatment of breast cancer.