WHY DO ANTICANCER DRUGS FAIL AND HOW MIGHT GENOMIC APPROACHES HELP ADDRESS THIS ISSUE?
For advanced cancers, nearly all cancer drugs eventually fail. This can occur at two stages: upon initial treatment and through recurrence of the cancer. Some patients do not respond to a drug initially even though genetic information suggested otherwise. This can be due to additional mutations present in the targets, which confer resistance, or because other cellular pathways are active in the tumor pathway, which counteract the treatment. One example involves EGFR. Patients with a common mutation in the EGFR gene (EGFR L858R) are sensitive to erlotinib; however, patients can have a second mutation (EGFR T790M) which confers resistance and thus they do not respond to the therapy. Therefore, understanding the complete picture is very important for treating these patients. In most cases, we do not understand why a set of patients do not initially respond to treatments and efforts are underway to identify the “bypass” mutations and pathways.
One of the major challenges of cancer treatment is that even if treatment makes a tumor stop growing or makes it shrink, as long as the tumor remains, drug-resistance nearly always emerges over time—even in cases in which treatment is highly targeted against a major driver of uncontrolled proliferation, such as mutant BRAF in melanoma. Sometimes resistance appears quickly and sometimes it emerges after several years. The emergence of drug resistance may be understood in the context of tumor heterogeneity. As discussed earlier in this article, the cells that compose a tumor are not genetically identical and new mutations arise as cancer cells grow. Additionally, previous chemotherapy efforts may cause new mutations to appear in a tumor that is not completely eliminated. Furthermore, all the cells that compose a tumor may not share the same gene expression pattern (even if they are genetically identical)—for example, differences in where they are located within the tumor may affect which genes are expressed. Certain genetic variants and certain gene expression profiles present in only one or a small number of tumor cells may make those cells less susceptible or resistant to the effects of an anticancer drug. In the presence of the drug, the less susceptible/resistant cells continue to grow and divide. They may even pick up additional mutations that further promote proliferation and/or make them more drug-resistant. Eventually there will be enough of these drug- resistant cells to make tumor growth detectable.
There are a variety of biological mechanisms underlying drug resistance that might be detected by tumor genome sequencing. For targeted drugs, resistance might be related to the presence of a subset of cells that do not express the target because they do not carry the driver mutation and/or carry additional mutations that alter the interaction of the drug with the target. To be effective, many drugs need to be internalized and accumulate within tumor cells. Drug resistance can be related to mutations that disable the mechanism by which the drug is internalized or hyperactivate the mechanism by which the drug is removed from cells. Drug resistance also might be related to genetic variants that activate compensatory mechanisms that offset the detrimental effect of a drug on a tumor cell (e.g., if a drug damages tumor cell DNA, repair mechanisms might be activated).
Combination therapy in which two or more drugs are administered together is common in cancer treatment and helps address tumor heterogeneity and the emergence of drug resistance. This is poorly understood in many cases, however, and efforts are underway to optimize combination therapies. In the future, it will be important to understand the exact genetic composition of each person’s tumor, its evolution, and the effectiveness of drug combinations based on this information so that individualized treatments can be prescribed most effectively.