What Is Cancer Developing RESISTANCE to Treatment? What Solutions Are Being Sought?

Today, in stage 4 (metastatic) cancers, alongside chemotherapy and hormone therapies, targeted smart drugs and  immunotherapies have been added. In metastatic cancers, in addition to surgery and radiotherapy, which are local treatments, numerous and varied systemic treatment options are now available.

Successful outcomes in cancer treatment are achieved every day. The development of new-generation drugs, innovations in surgery, and contributions from genetics have enabled the design of more effective, patient-specific treatments that have significantly extended patients' survival. Despite all these efforts, the most important problem encountered in some patients, described as treatment not working or a lack of response to treatment, is drug resistance. Resistance to treatment is seen not only with chemotherapy and hormonal cancer treatments, but also with targeted drugs and immunotherapy.

Targeted cancer therapies (generally monoclonal antibodies or small-molecule drugs) are drugs designed to interfere with specific molecules needed for tumor growth and progression. Conventional cytotoxic (cell-killing) chemotherapies rapidly kill dividing cells in the body, usually by interfering with cell division. The primary aim of targeted therapies is to fight cancer cells more precisely and with potentially fewer side effects.

Targeted therapy has some disadvantages:

• Developing drugs for some molecules targeted at the cellular level is difficult. This may be due to the target's structure, its function in the cell, or both.
• Cancer cells can alter their genetic structure by activating mechanisms that protect them under stress, becoming resistant to targeted therapy. These therapies may therefore work best when used in combination with other types of targeted therapy or other cancer treatments such as chemotherapy and radiation.

Two types of drug resistance occur in cancer:

1. Primary drug resistance: This occurs under the influence of certain factors before treatment. Genetic and epigenetic factors are thought to play a role in this situation.

2. Acquired drug resistance: This occurs during or after treatment. The cancer cell's “genetic” structure is not stable, so it rapidly mutates. A response to the drug is seen at the start of treatment, but resistance develops later.

Mechanisms of drug resistance in cancer are an area of intensive research, and many mechanisms lead to drug resistance:

• Epigenetics
• Inactivation of the drug
• Changing the drug target
• Epithelial-mesenchymal transition
• Inhibition of cell death
• DNA damage repair
• Pumping the drug out of the cell

Nature magazine's special issue “Milestones in Cancer” (Nature Milestones Cancer) devoted considerable attention to drug resistance in cancer. Detailed information on this subject is provided below:

What are the routes to resistance in cancer?

At the beginning of the millennium, drugs were developed that selectively targeted driver genes involved in cancer. For example, tyrosine kinase inhibitors such as imatinib were shown, by targeting BCR-ABL, a fusion gene with constitutive tyrosine kinase activity, in patients with advanced chronic myeloid leukemia (KML) to lead to sustained and lasting remission.

Note: A tyrosine kinase inhibitor is a synthetic drug that inhibits the group of enzymes called tyrosine kinases. Tyrosine kinases are enzymes responsible for activating many proteins through signal transduction pathways.

Unlike more conventional genotoxic treatments (such as chemotherapies), these drugs were believed to cause fewer side effects. With such precise targeted therapies, hopes were high that this new generation of drugs might represent the “magic wand / treatment” long sought by patients and doctors.

Unfortunately, the reality is not that simple

Although patients (even those with advanced disease or complex molecular changes) initially respond to these targeted drugs, a clinical trial with imatinib reported by Druker and colleagues showed that tumors in patients with acute lymphoblastic leukemia or KML in lymphoid blast crisis relapsed after daily treatment lasting several weeks or months. How cancer cells can adapt to specific strategies that directly target fundamental cancer mechanisms is still being discussed and investigated.

Mercedes E. Gorre, Charles Sawyers, and colleagues set out to answer this question. Imatinib is known to work by binding the BCR-ABL kinase domain, thereby blocking its function. Because earlier work by Chin and colleagues had shown that cancers generally require the activity of their primary oncogenes (a type of cancer gene), Gorre and colleagues wondered whether imatinib-resistant tumors would still depend on the BCR-ABL fusion gene. They reasoned that, if relapsed tumors were still dependent on BCR-ABL, BCR-ABL signaling activity would remain evident even after treatment. Because the BCR-ABL protein breaks down rapidly, they measured phosphorylation of CRKL, one of its downstream targets. Indeed, CRKL phosphorylation in tumors from 11 patients with relapse was almost as high as in untreated patients.

Stimulation without a stimulus (growth factor)

The next step was to determine what allowed BCR-ABL to remain active. The authors concluded that an intracellular factor was responsible because relapsed cells isolated from patients still displayed this oncogenic activity, suggesting that no external growth factor was involved. The authors examined changes in the BCR-ABL gene and found two strikingly different escape mechanisms in different patients.

The first resistance-associated change can be understood as an all-out, brute-force approach to fighting the inhibitor: tumors in three patients with relapse had produced many copies of the BCR-ABL gene through gene amplification (multiplication). The copy number increased with subsequent lines of treatment; however, in one patient these amplifications disappeared after switching to another treatment, suggesting that the drug selected for clones carrying the amplification.

Drug-escape mutations

In contrast, the second resistance mechanism required a single modification: a point mutation changing threonine 315 of ABL1 to isoleucine was found in six patients. Because this particular amino acid is critical for imatinib binding, the mutation abolished binding to the drug. Unlike wild-type (natural phenotype) BCR-ABL, this mutant retained its activity in cell lines even after exposure to the drug.

The evolution of cancer

This study, together with similar studies published shortly afterward, including the discovery by Kobayashi and colleagues of EGFR mutations conferring resistance to gefitinib in lung cancer, illustrates several important aspects of cancer. On the one hand, these data show that cancer is an evolutionary process: under strong selective pressure, cells with adaptations that allow them to overcome an adverse environment will prevail.

• Related topic: What is cancer evolution? (in detail) 

Could treatment-resistant cells also be present in the initial tumor?

Such cells may actually already be present in the initial tumor. Even seemingly homogeneous cancers can harbor genetically heterogeneous (mixed) cell populations that have an advantage in the 'arms race' against therapy, as described by Dagogo-Jack and Shaw. In addition, resistance can be achieved through distinctly different but functionally convergent approaches. On the other hand, these studies also revealed a critical feature of cancers: certain genes and mutations remain fundamental drivers / triggers of tumor growth and survival.

Steps toward a solution

Knowing and targeting the central drivers of drug resistance remains an important clinical strategy used to develop new generations of clinically effective tyrosine kinase inhibitors.

Targeted therapies will remain an important part of the arsenal against cancers, particularly when tested in different combinations that may prevent resistance to a single drug. The roles of off-target, non-genetic mechanisms in this resistance are also beginning to be recognized and will need to be addressed through appropriately tailored approaches. As long as the design and use of these treatment strategies are guided by evolutionary principles, our hope is that drug resistance in patients will one day be predicted and avoided.

Conclusion

Alongside chemotherapy and hormone therapy, targeted therapies (monoclonal antibodies and small-molecule drugs) and immunotherapies now have an important place in treating cancers, with advances in genetics also contributing. Research into combination drug therapies and genetic and non-genetic mechanisms offers hope that drug resistance may one day be overcome.