It’s an all-too-common story within cancer care: a patient enters remission, only to discover a few months later that their tumour has returned. Just as bacterial infections can become resistant to antibiotics, cancer cells can find a way to evade the treatment, leading to disease recurrence.
This is as much a problem now as it ever was. While the last few years have seen huge advances in oncology, the new drugs aren’t necessarily superior at fending off resistance.
“Cancer drug resistance is THE central problem across the entire oncology space,” says Dr Janusz Rak, a professor in the department of paediatrics at McGill University. “In fact not only has this problem not gone away but it continues to beset traditional treatment modalities such as chemotherapy, as well as novel therapies.”
He adds that this applies to biologics and anti-angiogenics (i.e., drugs that work by cutting off the blood supply), among many other classes of treatment.
“Immunotherapy could be one possible exception, but only in the small fraction of patients where cancers are actually cured,” he says.
The big question is why this happens. After all, if we fully understand the mechanisms underpinning resistance, we stand a better chance of outfoxing the cancer cells and eradicating them altogether.
Unfortunately, there are no simple answers. Since tumours are genetically unstable, with cells quick to acquire mutations, a drug may kill some – but not all – of the cell population. Only the drug-resistant cells remain, and those are the ones that will proliferate.
“Cancer cells are more heterogeneous and adaptable than our drug discovery process is capable of dealing with,” says Rak. “This is why spectacular responses to very powerful and ‘smart’ anticancer agents are often temporary as cancer stem cells continue to evolve to avoid these agents.”
Strictly speaking, there are two types of drug resistance. The first is acquired resistance, where a treatment is initially effective but then stops working. The second is intrinsic or ‘de novo’ resistance, where cancers are resistant from the outset.
“We don’t understand cancers well enough, so we come up with agents that simply don’t work a priori, even though they should. Or they might work in some patients, but not all,” says Rak.
In both cases, the mechanisms are diverse, with cancer cells often deploying several evasion tactics simultaneously.
As well as DNA mutations and metabolic changes, these tactics can include increased drug efflux (where the drug is expelled from the cell before it can reach its target) or DNA damage repair (where cells develop the ability to ‘repair’ the damage caused by chemotherapy). We might also see drug target alteration, increased expression of target proteins and evasion of cell death.
Although scientists now know a great deal about these mechanisms, individual patients may represent unique scenarios, meaning it can be be hard to work out what is happening.
“In a more general sense, we may have not yet come up with workable options to overcome or circumvent the emerging resistance without causing too much damage,” adds Rak.
So with cancer drug resistance still vexing researchers, what can be done? Despite his assessment of the challenges, Rak feels they can be overcome.
“Before 2001 chronic myeloid leukaemia (CML) was a ‘resistant’ cancer, but it has become a treatable one with imatinib and similar agents. There are cures and long-term responses across many cancer types that once were hopeless,” he explains.
To look at this example in more depth, imatinib is a site-specific therapy that works by inhibiting a certain enzyme. It has been touted as revolutionising the CML treatment landscape, and has brought the estimated five-year survival rate up to 90%.
Although some patients do eventually develop resistance (or are resistant from the outset), this is by no means always the case. What’s more, a new generation of targeted drugs are emerging as a secondary treatment option for these patients.
Of course, no treatment is infallible, and combination therapies are often better placed than single ones to mitigate drug resistance. Through taking a number of different drugs (either all at once or in a particular order), it is possible to exploit different weaknesses in the cancer cells and overcome multiple evasion mechanisms.
Many scientists are working on novel drug combinations, sometimes including drugs that are indicated for other diseases. For instance, in recent lab tests, metformin (used to treat type 2 diabetes) was found to prevent or delay resistance to doxorubicin (a chemotherapeutic used for breast cancer).
There is also an emerging field of research surrounding epigenetics. Some scientists now think that, far from being a completely disorganised process, the development of cancer stems in part from epigenetic changes. Drug resistance may function similarly.
Dr Sibaji Sarkar of the Boston University School of Medicine is one of the leading researchers in this field. He believes that, while target-specific drugs are essential for halting cancer’s growth, these should be combined with epigenetic drugs to prevent recurrence.
“If epigenetic mechanisms play a significant role in cancer progenitor cell formation and cancer drug resistance, introduction of epigenetics drugs, with conventional therapy, should reduce the chance of cancer relapse,” he says. “A thorough standardisation is necessary depending on the combination of drugs, different types of cancers and individual patient situation.”
Harnessing the immune system
Within the immunotherapy space, drug resistance remains something of a mystery. Often regarded as the biggest cancer breakthrough in recent years, immunotherapy kills cancer cells by mobilising the immune system.
The early hope was that the approach would be less evadable by cancer cells, given that it harnesses the body’s own defences. However, some patients do still experience disease recurrence.
“It’s a major area of unmet need and the focus of active investigation,” says Dr Jeffrey Weber, deputy director of the Perlmutter Cancer Center. “The tumour microenvironment has many suppressive influences, which along with the adaptive resistance of the tumour makes it very difficult for immune therapy to work in a proportion of patients.”
There could be a few issues at play here – either the immune system is failing to function, or the tumour cells themselves are becoming resistant. (As many researchers see it, it’s probably a combination of both.)
One point that seems to be relevant here is the difference between ‘hot’ and ‘cold’ tumours – i.e. those that are filled with immune cells and those that are not. Hot tumours are more easily able to respond to treatment without developing resistance.
“With immunotherapy, making a cold tumour ‘hot’ is likely to be the best way to augment the ability of our treatments to mediate the regression of the tumour,” says Weber.
Rak feels that the patient’s immune system will remain an important ongoing subject of research. After all, the immune system is fast and versatile – crucial traits when trying to deal with the moving target of mutating cancer cells. Immunotherapy drugs are designed to to give it the push it needs.
“In my view we need to know more, not just about individual cancer cells, but about how their populations are organised and change the body’s responses. I think we are heading in that direction,” he says.