Treating Cancer: Tackling Drug Resistance

One of the biggest barriers to treating cancer is drug resistance, a phenomenon that remains only partially understood. This is partly because of the complex ways in which different forms of cancer are treated, and partly because of how quickly cancer cells can adapt and change to the environment around them.

The resistance of cancer to certain drugs is thought to have come about the same way cancer itself was born; through evolution. Mutations can cause cancers to be resistant to drugs, in the same way resistance to antibiotics is created in certain strains of bacteria. However, there is also a body of evidence coming to light that suggests there could be non-genetic mechanisms through which cancer can also develop resistance to drugs.

While drug resistance has been a problem in cancer for years, new treatments are coming to light that could help overcome it. For example, a recent paper published in Nature Communications details a way to use a combination of infrared lasers and nanoparticles to cause cancer cells to lose their drug resistance capability, providing a ‘window’ for chemotherapy to become effective.

Drug resistance: Chemotherapeutics

Just like a multicellular organism, cancerous tumors evolve. Tumors grow by cell division, and each time a new cell is created there is an opportunity for evolution. The key difference is, they can evolve at a much faster rate than organisms, and this is what makes it so difficult to develop cancer treatments. Tumors begin as one cell which is subsequently cloned over and over again, but during the cloning process mutations can occur. If a genetic mutation occurs that makes that cell resistant to a chemotherapeutic drug, in one way or another, that cell will survive, and undergo further cell cloning, creating a tumor that is drug resistant.

Chemotherapeutic drugs are cytotoxic agents, meaning they attack both cancerous and noncancerous cells that are in the process of dividing.  This usually works by interfering with a cell’s production of new DNA as it starts to divide. However, this approach can be dangerous when there are drug-resistant cancer cells involved. “…Resistant cells can run wild after cytotoxic drugs clear out all the competitors,” said Carlo Maley, from the University of San Francisco, in a press release in 2011.

For example, a common chemotherapeutic drug 5-fluorouracil (5-FU), targets the thymidylate synthase (TYMS) genetic pathway. In 2004, however, it was shown that resistance can evolve through the evolution of extra copies of TYMS, which reduces the effectiveness of the drug. Another example of resistance in chemotherapeutic drugs, and one of the first examples to be discovered, is resistance to methotrexate, which inhibits dihydrofolate reductase (DHFR), leading to amplification of the DHFR gene. For tumors treated with methotrexate, mutations occur - with amplification of DHFR, which ultimately reduces the drug’s effectiveness.

Looking into how cancerous tumors evolve and change is key to tackling cancer, says Maley, because of how quickly resistance to a certain drug can develop. For example, a combination of treatments that also works to slow down the evolution of a tumor would lower the chances of a drug-resistant mutation occuring. “We tend to judge the immediate effects of treatment on tumor size, but what’s really important is patient survival,” Maley says. “A drug might not quickly shrink a tumor measurably, but that would not matter down the road if the patient never relapses.”

Drug resistance is not just a problem when it comes to chemotherapy, in fact some form of resistance has been observed for almost every form of therapy developed for treating cancer. Resistance can take several forms, including mutations that stop the drug from binding to its target, amplification of proteins that compensate for the loss of the target, or via activation of other biological mechanisms.

Drug resistance: Targeted treatments

A major breakthrough in cancer treatment came in 2001, with the development of a compound called imatinib mesylate, also known by its commercial name Gleevec^® or Glivec^®. The drug targets the BCR-ABL fusion gene and is used mainly for cases of chronic myeloid leukemia (CML). When it was first developed, imatinib mesylate was described as the answer to CML, particularly because it produced few side effects. However, resistance to the drug has been seen through a mutation that changes the shape of the active site of BCRTrav3l-ABL, where the drug binds, rendering it no longer effective.

Another type of targeted therapy, used for lung cancer, is epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. They work by interrupting the signaling through the EGFR gene. Two examples of this kind of drug are gefitinib and erlotinib, however research has shown most patients’ tumors become resistant to the drugs over time. In 2013, the US Food and Drug Administration (FDA) approved a tumor tissue test to look for EGFR mutations, to see what kind of resistance might already be present before trying an alternative therapy.

Research in 2008 found there are two known ways this resistance can happen; through mutations in the EGFR gene and through the amplification of MET, a proto-oncogene that also encodes a receptor tyrosine kinase. When cancer develops, the MET pathway can be activated, which leads the signaling to bypass the EGFR pathway, that has been inhibited by the original drugs. Research is underway to find a way to further understand how MET amplification occurs, and how to prevent it. A review paper in 2014 concluded that: “Accumulating preclinical and clinical evidence thus suggests that MET amplification is an ‘oncogenic driver’ and therefore a valid target for treatment. However, the prevalence of MET amplification has not been fully determined, possibly in part because of the difficulty in evaluating gene amplification.”

Developing new drugs is one solution to the problem, but the difficulty is how quickly cancerous cells can evolve to become resistant to the new drugs. In 2015, a drug called osimertinib, also known as Tagrisso^®, was approved by the FDA, to target cells that had already become resistant to the first generation of EGFR inhibitors. However, in the same year, studies had already identified a C797S mutation which rendered cells resistant to the new therapy.

Drug resistance: Anti-androgen therapies

Male hormones called androgens are the driving force behind most prostate cancers, by stimulating cell division. Because of this, most treatments for prostate cancer involve blocking or removing these androgens and is termed ‘anti-androgen therapy’. In prostate cancer, drug resistance works in a different way to targeted drugs like EGFR inhibitors. Instead of a genetic mutation that makes the androgens resistant to being blocked or removed, mutations in the androgen receptors make the receptors ultra-sensitive to the few androgens that do remain. On top of this, some cases of anti-androgen therapy resistance have seen extra copies of the androgen receptor gene being created.

Overcoming drug resistance in cancer

One of the most obvious ways of beating drug resistance is by creating more drugs, to give doctors a greater chance of being able to tackle a tumor. “I’ve been saying this for 15 years: [beating cancer] takes time, and we need more drugs,” Charles Sawyers, New York City’s Memorial Sloan Kettering Cancer Center, told The Scientist in April 2017.

While some drug resistance in cancer is related to gene mutations in the tumor itself, other causes are epigenetic which means they could, in theory, be overcome, according to a literature review published in February 2018, “at least in some cases, refractoriness to treatment can be reversed by epigenetic reprogramming, and combination and intermittent therapies, as opposed to sustained monotherapy, appear more effective in attenuating it,” say the authors, led by Dr Ravi Salgia from the City of Hope's Comprehensive Cancer Center in Los Angeles, California.

However, the review adds that there is still “confusion in understanding the phenomenon by which cancer cells evade drug response” and emphasizes the importance of understanding exactly how drug resistance is developed in cancer, in particular a focus on both genetic and non-genetic factors.