The first group of drugs were membrane RTK inhibitors that spanned the cell membrane, with a ligand-binding extracellular domain outside the cell, and inside the cell, an intracellular kinase domain.¹²² MAbs are effective in blocking ligand binding, which prevents the message from being generated. If it is not blocked, ligand binding and receptor dimerization activate the message and it is sent across the cell membrane to the intracellular kinase, which can be blocked by small, oral tyrosine kinase inhibitors. These strategies to blocking the EGFR RTK either at the external domain of the receptor (e.g., via cetuximab) or the internal domain (tyrosine kinase, e.g., via erlotinib) have been discussed previously (see Figure 2-5).

Other strategies could be neutralization of the ligand, but if the ligand is critical for other human body functions, such as cellular repair, it cannot always be neutralized. We will see in Chapter 3 that neutralizing the ligand VEGF is an effective strategy. As we saw in the families of these receptors, there were multiple pathways within the cell that became activated as the message made

its way like a bucket brigade downstream to the cell nucleus. Once the message reaches the nucleus, there are transcription factors in the nucleus that may also be abnormal from the malignant transformation, and the malignant process accelerates. This section will address the proteins involved in taking the message to the cell nucleus, the secondary messengers in the cytoplasm. There are other secondary messengers, such as calcium, but these will not be discussed. An example of a protein kinase that is a secondary messenger is that in Philadelphia chromosome-positive (Ph+) chronic myelocytic leukemia (CML), BCR-Abl, which is blocked by imatinib mesylate (Gleevec).² In addition, imatinib mesylate blocks c-kit and PDGFR.