Conference report--protein kinase inhibitors in cancer treatment: mixing and matching? Highlights of the keystone symposium on protein kinases and cancer; February 24-29, 2004; Lake Tahoe, California. (2004)

With the success of imatinib in the treatment of patients with chronic myelogenous leukemia (CML), “targeted” or “rational” therapies have become a hot topic in oncology. Imatinib inactivates the kinase activity of BCR-ABL, the fusion protein that causes CML. Can other oncogenic kinases be targeted in a similar manner?

Protein kinases play important roles in regulating most cellular functions — proliferation/cell cycle, cell metabolism, survival/apoptosis, DNA damage repair, cell motility, response to the microenvironment — so it is no surprise that they are often themselves oncogenes. Kinases such as c-Src, c-Abl, mitogen activated protein (MAP) kinase, phosphotidylinositol-3-kinase (PI3K) AKT, and the epidermal growth factor (EGF) receptor are commonly activated in cancer cells, and are known to contribute to tumorigenesis. Many of these occur in the same signaling pathway — for example, HER-kinase family members (HER1 [EGFR], HER3, and HER4) transmit signals through MAP kinase and PI3 kinase to promote cell proliferation.

Research groups have developed several ways to target these enzymes therapeutically, such as with antibodies or small molecules that block kinase-substrate interaction, or that inhibit the enzyme's adenosine triphosphate (ATP) binding site. A number of kinase inhibitors have therefore already been developed and approved for cancer treatment. These include inhibitors of c-Abl (imatinib, for treatment of CML), HER2 (trastuzumab, for treatment of breast cancer), vascular endothelial growth factor receptor (bevacizumab, for treatment of metastatic colorectal cancer), and the EGF receptor (gefitinib, cetuximab, for treatment of lung and colorectal cancer). Many other drugs are currently being tested in cancer clinical trials for their ability to target kinases.

The potential for targeting kinases in the treatment of cancer was the theme of the Keystone Symposium “Kinases and Cancer: The Promise of Molecular Based Therapies” recently held in Tahoe City, California.

In the opening address, Robert Wittes,[1] of the Memorial Sloan-Kettering Cancer Center, New York City, NY, discussed the pros and cons of targeting kinases in cancer patients. Kinase inhibitors designed to block the enzyme's ATP binding site can have broad specificity — imatinib not only inhibits the tyrosine kinase c-Abl, but also c-Kit and the platelet-derived growth factor (PDGF) receptor tyrosine kinases. So it can be used to treat gastrointestinal stromal and other types of tumors associated with activation of these signaling molecules.

Additionally, unlike cytotoxic drugs, many kinase inhibitors have been found to have low levels of toxicity in preclinical and clinical studies. Exceptions have been seen with trastuzumab, which can cause cardiac damage; bevacizumab, which has been associated with pulmonary bleeding; and gefitinib, which can cause interstitial lung disease. Of note, the long-term side effects of kinase inhibition are not known. Resistance may also be an issue, as many patients who were treated with imatinib have since become resistant, due to mutations in c-Abl. Kinase inhibitors might therefore be most effective if administered in combination.[1]