Receptor Tyrosine Kinase Inhibition

By far the most successful approach to targeting the RAS pathway in cancer has been to develop inhibitors of upstream activators of RAS. The development of inhibitors for specific RTKs limits the utility of these drugs to cancers where that particular RTK is overactive, but given these constraints, this class of drugs seems highly effective. RTKs play prominent roles in many cancers, ranging from non-small cell lung cancer to breast cancer to gastrointestinal stromal tumors, which often feature activation/overexpression of EGFR, ErbB2/HER-2, and c-Kit, respectively.22'26 Additionally, the Bcr-Abl oncoprotein, which causes chronic myelogenous leukemia, can mimic RTK signaling. The fusion of Bcr to c-Abl redistributes the normally nuclear c-Abl activity to the cytoplasm, where it can activate RAS.

Drugs using two different mechanisms of action have been used successfully against the upstream activators. First, herceptin, a humanized antibody against the extracellular domain of Erb2, has been used in treating Erb2/HER2/Neu-positive breast cancers. Erb2 is the most highly active EGFR family member, and although there is no known ligand for Erb2, activation of other EGFR family receptors by ligand binding results in their heterodimerization with Erb2 and increased signaling potential.21,26 The antibody stops the transmission of signals to RAS before they start by binding Erb2, blocking dimerization and activation, and stimulating internalization and degradation of the receptor.26 Herceptin may also contribute to immune responses against tumors, as demonstrated by the increased effectiveness of herceptin with a complete Fc region of the antibody. Several other humanized antibodies have been approved for use in targeting RTKs; erbitux targets EGFR, whereas avastin targets vascular endothelial growth factor receptor (VEGFR).

The second class of drugs is small molecule inhibitors of the tyrosine kinase activity of receptors such as PDGFR and EGFR, which have been targeted for inhibition successfully with gleevec and iressa.26 Gleevec is the final product of a screen that began looking at modified ATP competitive inhibitors of PKC-a for the inhibition of PDGFR, which is activated in many tumors. Although it was designed as an inhibitor or PDGFR, it functions against RTKs related to PDGFR, such as c-Kit. Surprisingly, it also was found to be effective against the Bcr-Abl fusion protein. When used in the treatment of cancers resulting specifically from activations of c-Kit and Bcr-Abl, such as gastrointestinal stromal tumors and chronic myelogenous leukemia, respectively, gleevec has been wildly successful.26 Iressa, a small molecule inhibitor of EGFR, has also been a successful treatment in non-small cell lung cancer, and inhibitors of several other RTKs involved in cancer, such as FLT3, are under development.20

Although antibodies and small molecules targeting RTKs are effective, they have limited utility for the treatment of multiple cancers, as the targeted RTK must be activated in a tumor for the drugs to have an effect. For instance, herceptin is only beneficial in breast cancers expressing Erb2, which encompass only 30% of all breast cancers.26 Even further specificity has recently been shown with non-small cell lung cancers and iressa. The target of iressa, EGFR, is expressed in the tumors of multiple patients, but the best response is seen only in a subset of patients who have somatic mutations in the kinase domains of EGFR.18,19 This exquisite sensitivity has also been reported for gleevec treatment of tumors containing c-Kit mutations. Taken together, the examples of herceptin, iressa, and gleevec, show that inhibition of RTKs is extremely effective only when the expression pattern and mutations of the receptors in any given tumor are known.

Although much is known about the core cell-cycle machinery and the alterations of the machinery in cancer, many modifiers of these proteins, either upstream or downstream, and their connection to the core cell-cycle machinery remain a mystery. Further research into these areas will present new targets for the rational design of drugs to combat cancer. The continued development of effective cancer treatments is dependent upon a further understanding of the pathways that lead to cancer, the development of drugs that inhibit these pathways, and the ability to determine which drugs to use against specific cancers or even the tumors of specific patients.

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