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The success of the original kinase inhibitors had raised hope that drugs that target key kinases underlying other cancers, such as members of the human epidermal growth factor receptor (HER) family, might be similarly efficacious. However, several small-molecule inhibitors of HER family kinases have shown limited efficacy in HER2-driven breast cancers, despite effective inhibition of kinase activity. An article in Nature, 7 Jan 2007, scientists had provided an explanation for this phenomenon: failure to completely inhibit the kinase activity of HER2 allows oncogenic signaling through the kinase-inactive family member HER3 to continue.

Signaling in the HER family, which consists of epidermal growth factor receptor (EGFR), HER2, HER3 and HER4, involves receptor dimerization and transphosphorylation, which leads to the activation of various pathways, including the potentially oncogenic phosphatidyl-inositol 3-kinase (PI3K)/Akt pathway. While these agents are effective at inhibiting EGFR and HER2 phosphorylation in patients' tissues and tumors, Akt activity is not inhibited as might be anticipated in many patients, which could explain the limited clinical activity of the drugs.

Patients with HER2-positive breast cancer being treated with anti-HER2 therapy may be able to prevent or delay resistance to the therapy with the addition of a PI3K kinase inhibitor to their treatment regimens. Dual simultaneous inhibition of both HER2 and PI3K may prolong the use of anti-HER2 therapies in women with breast cancer. Designing 'targeted' anticancer drugs begins with identifying the genes or proteins that are specific to the development of cancer and testing whether blocking those genes or proteins gets rid of the cancer. Genetic (molecular) tests are instrumental in accomplishing this task.

However, understanding 'targeted' treatments begins with understanding the cancer cell. Every tissue and organ in the body is made of cells. In order for cells to grow, divide, or die, they send and receive chemical messages. These messages are transmitted along specific 'pathways' that involve various genes and proteins in a cell.

Genetic-based testing examines a single process within the cell or a relatively small number of process. The aim is to tell if there is a theoretical predispostion to drug response. Phenotype analysis not only examines for the presence of genes and proteins but also for their 'functionality' (their interaction with other genes, proteins, and processes occurring within the cell, and for their response to 'targeted' drugs).

Genetic-based testing involves the use of dead, formaldehyde preserved cells that are never exposed to 'targeted' drugs. Genetic-based tests cannot tells us anything about uptake of a certain drug into the cell or if the drug will be excluded before it can act or what changes will take place within the cell if the drug successfully enters the cell.

Genetic-based tests cannot discriminate among the activities of different drugs within the same class. Instead, it assumes that all drugs within a class will produce precisely the same effect, even though from clinical experience, this is not the case. Nor can Genetic-based tests tell us anything about drug combinations.

Phenotype analysis (functional profiling) looks at 'fresh' living cancer cells. It assesses the net result of all cellular processes, including interactions, occurring in real time when cancer cells actually are exposed to specific anti-cancer drugs. It can discriminate differing anti-tumor effects of different drugs within the same class. It can also identify synergies in drug combinations.

When considering a 'targeted' cancer drug which is believed to act only upon cancer cells that have a specific genetic defect, it is useful to know if a patient's cancer cells do or do not have precisely that defect. Although presence of a 'targeted' defect does not necessarily mean that a drug will be effective, absence of the targeted defect may rule out use of the drug.

As you can see, just selecting the right test to perform in the right situation is a very important step on the road to personalizing cancer therapy. Sometimes a drug will inhibit the 'target' but not stop the growth of cancer. Not all genes and proteins have a critical role in the survival and growth of cancer cells.

The are many pathways to altered cellular (forest) function, hence all the different 'trees' which correlate in different situations. Improvement can be made by measuring what happens at the end of all processes (the effects on the forest), rather than the status of the individual trees (pathways/mechanisms). You still need to measure the net effect of all processes, not just the individual molecular (gene/protein) targets.

You can see why laboratory oncologists like Drs. Nagourney and Weisenthal have been interested in this. Nagourney will be presenting some information about the comparisons of various kinases.

Robert A. Nagourney, Paula J. Bernard, Eric Federico, Sophie Nguyen, Steven S. Evans.

Presentation Abstract Number: 3525

Presentation Title: Functional analysis of epidermal growth factor receptor tyrosine kinase inhibitors: A comparison of Afatanib, Lapatinib, and Gefitinib in human tumor primary cultures.