Why Do Some Lung Cancers Stop Responding to Tarceva?

[gpawelski]

Tarceva is a targeted therapy, in that it halts the growth of certain cancers by zeroing in on a signaling molecule critical to the survival of those cancer cells. The drug is effective in about 10-15% of patients with non-small cell lung cancer. The drug works specifically in patients whose cancers contain mutations in a gene that encodes the epidermal growth factor receptor (EGFR). Lung cancer patients with these mutations are often people who have never smoked.

Although this targeted therapy is initially effective in a subset of patients, the drug can eventually stop working, and the tumor begins to grow again. This is called acquired or secondary resistance. This is different from primary resistance, which means that the drug never worked at all. The change of a single base in DNA that encodes the mutant EGFR protein has been shown to cause drug resistance.

The T790M mutation has been thought to cause resistance by sterically blocking binding of small molecule tyrosine kinase inhibitors such as Iressa and Tarceva. Drug resistance evolves by multiple mechanisms.

Initially, tumors have the kinds of mutations in the EGFR gene that were previously associated with responsiveness to these drugs. But, sometime tumors grow despite continued therapy because an additional mutation in the EGFR gene, strongly implies that the second mutation was the cause of drug resistance. Biochemical studies have shown that this second EGFR mutation (T790M), which was the same as before, could confer resistance to the EGFR mutants normally sensitive to these drugs.

It is especially interesting to note that the mutation is strictly analogous to a mutation that can make it tumor resistant. Non-small cell lung cancer makes up about 80 percent of all lung cancers. Mutations in a gene called KRAS, which encodes a signaling protein activated by EGFR, are found in 15 to 30 percent of these cancers. The presence of a mutated KRAS gene in a biopsy sample is associated with primary resistance to these drugs.

Tumor cells from patients in a study who developed secondary resistance to Tarceva after an initial response on therapy did not have mutations in KRAS. Rather, these tumor cells had new mutations in EGFR. This further indicates that secondary resistance is very different from primary resistance.

All the EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if Tarceva is better or worse than Iressa or some other drug which may target this. There are differences. The drug has to get inside the cells in order to target anything.

EGF-targeted drugs are poorly-predicted by measuring the ostansible target EGFR, but can be well-predicted by measuring the effect of the drug on the 'function' of live cells. A cell-based targeted therapy profile includes analysis of the following targeted drugs: Tarceva, Iressa, Nexavar, and Sutent.

Literature Citation:

PLoS Medicine, February 22, 2005

Eur J Clin Invest 37 (suppl. 1):60, 2007

[gpawelski]

The headlong rush to develop pre-tests (companion diagnostics) to identify molecular predisposing mechanisms still does not guarantee that a cancer drug will be effective for an "individual" patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different cancer agents of the same class.

The drug discovery model over the last three years or so has been limited to one gene (protein), one target, one drug. The "cell" is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyse the systems' response to drug treatments, not just one target or pathway.

With all the hoopla of decoding the human genome in 2000, sparked hopes that a new era of tailored medicine was just around the corner. However, uncovering the genetic differences that determine how a person responds to a drug, and developing tests, or biomarkers, for those differences, is proving more challenging than ever. As a result, patients with cancer are still being prescribed medicines on a trial-and-error basis.

The key to understanding the genome is understanding how cells work. The ultimate driver is "functional" pre-testing (is the cell being killed regardless of the mechanism) as opposed to "target" pre-testing (does the cell express a particular target that the drug is supposed to be attacking).

While a "target" test tells you whether or not to give "one" drug, a "functional" pre-test can find other compounds and combinations and can recommend them from the one test.

The core of "functional" testing is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a "targeted" drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell. Both genomics and proteomics can identify potential new thereapeutic targets, but these targets require the determination of cellular endpoints.

Cell-based "functional" pre-testing is being used for screening compounds for efficacy and biosafety. The ability to track the behavior of cancer cells permits data gathering on functional behavior not available in any other kind of testing.

Gene profiling tests, important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for "individual" patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess.

It will never be as effective as the cell "function" methodology, which has existed for the last twenty years and is not hampered by the problems associated with gene expression tests. That is because they measure the net effect of all processes within the cancer, acting with and against each other in real-time, and it tests "living" cells actually exposed to drugs and drug combinations of interest.

It would be more advantageous to sort out what's the best "profile" in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones and "personalize" their treatment. If one drug or another is working for some patients then obviously there are others who would also benefit. But, what's good for the group (population studies) may not be good for the individual.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with "best guess" empiric chemotherapy through clinical trials.

It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

All the validations of this gene or that protein provides us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, but if the "targeted" drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work.

To overcome the problems of heterogeneity in cancer and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy in individual patients. This can be done by testing "live" tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell function analysis.

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate new medicines and treatments for cancer. More emphasis should be put on matching treatment to the patient, through the use of individualized pre-testing.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of "live" fresh tumor cell, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

[gpawelski]

There is a challenge to identify which patients targeted treatments like Tarceva will be effective. Initially, when Tarceva was used in patients with lung cancer, researchers discovered that only patients whose tumors contained specific mutations responded to the drug. But this may not necessarily be true. Patients across a broad range of clinical characteristics could benefit.

The FDA approved indication for Tarceva does not limit prescribing specifically to EGFR positive patients. In the registration trial, only one third of the patients were tested for EGFR and determining response based on EGFR was not a major endpoint of the study.

Testing for the EGFR mutation may be able to tell you whether or not your cells are "potentially" susceptible to this mechanism of attack. It cannot tell you if Tarceva will work for "your" individual cancer cells. It is still a "trial-and-error" approach to therapy.

Rather than only give Tarceva to all patients with EGFR+ NSCLC, it could be given selectively to patients with all types of cancer, if it otherwise indicated and if a functional assay is positive for it. It could be vastly more beneficial to measure the net effect of all processes (systems) instead of just individual molecular targets.

The cell is a system, an integrated, interacting network of genes, proteins, and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just one or a few targets (pathways/mechanisms).

There are many pathways/mechanisms to the 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 (the effects on the forest), rather than the status of the indivudal trees.

[gpawelski]

You have patients not just with lung cancer, but with virtually all solid tumors who are potential candidates for EGFR targeted therapy.

There are advantages in having cells which you can define as Tarceva/Iressa sensitive or resistant and studying what exactly is different. Then there is testing to circumvent resistance. Then there is testing combinations.

Rather than only give Tarceva/Iressa to all NSCLC patients with EGFR positive mutation, it could be given selectively to patients with all types of cancer, if it otherwise indicated and if a functonal profiling assay is positive for it.

These scientists hoped that inhibiting these enzymes might also be a possible treatment for other cancers in which members of the EGFR family are active. In addition to EGFR, the family consists of Her2, Her3, Her4, and these are implicated in a number of cancers such as lung, colorectal, head and neck and pancreatic cancers.

The KRAS marker appears to have a stonger correlation to ovarian cancer. So they can test for the KRAS gene mutation for ovarian cancer. Tarceva or Erbitux for ovarian cancer? Maybe?

Until recently, cancer treatment was ususally based on the tumor's location, such as the lung or breast. Doctors are now starting to consider the biology of the tumor cell along with the site of the tumor when determining treatment. They are learning that the same proteins and pathways are involved in many types of cancer.

Cell function analyses have performance characteristics that are reproducible, favorable and provide useful information to treating physicians. What's more, the information is the result of a clinical trial in which NSCLC patients underwent a functional profiling assay as part of a Phase II assay-directed trial (IRB-approved). It so happens that these patients were found more sensitive to Tarceva than to other forms of chemotherapy, all of which were tested for the same $3,500 price.

It costs well in excess of $1,000 to do EGFR mutation and FISH for amplification. All of which tells you whether or not to give Tarceva (one drug). Cell function analyses more often find NSCLC patients sensitive to other compounds and combinations and can recommend these all from one assay. It costs a lot more to give a single cycle of chemotherapy than it does to test all of the possible options.