Cancer is a good example. Early detection through tests like mammograms and CT scans has enabled doctors to treat tumours before they grow or spread. As a result, many patients have a better chance of recovery. Treatments have also improved greatly. In the past, chemotherapy—the most common option—was used to kill fast-growing cells, including cancer cells. But because it couldn’t tell the difference between cancerous and healthy cells, patients often experienced side effects like hair loss or nausea. Today’s targeted therapies, however, are more precise. They block specific signals that tumours need to grow or help the immune system attack cancer cells, minimising harm to healthy tissues. These new treatments have improved outcomes and reduced side effects for many patients.

Still, cancer treatment is not always successful, and drug resistance can lead to relapse. For example, Hollywood actress Shannen Doherty, best known for her roles in “Beverly Hills 90210” and “Charmed”, fought breast cancer for nine years. She underwent both chemotherapy and hormonal therapy, the latter being a targeted treatment that blocks hormones like oestrogen, which can fuel certain types of breast cancer. Initially, Doherty’s cancer went into remission in 2017, but it returned two years later as metastatic, or stage-four, breast cancer. Sadly, she passed away in July 2024.

Another well-known actress and singer, Olivia Newton-John, who starred in the hit movie “Grease”, also battled cancer. She was first diagnosed with breast cancer in 1992 and underwent chemotherapy and a partial mastectomy, a procedure in which part of the breast is surgically removed. Although she remained cancer-free for over 20 years, the disease returned and eventually spread to other parts of her body. Newton-John passed away in 2022, after living with metastatic cancer for several years.
 

The perpetual treatment arms race with cancer

The stories of Olivia Newton-John and Shannen Doherty underscore the relentless challenge posed by cancer’s ability to resist treatment. Their journeys illustrate how cancer can lie dormant for years, evading therapies only to resurface in a more aggressive form. This resistance often stems from the cancer cells’ ability to adapt and mutate, becoming impervious to the effects of initially effective drugs.

In breast cancer, resistance is a formidable challenge in both chemotherapy and targeted therapies, such as hormone treatments or HER2 inhibitors. Tumour cells develop mechanisms to avoid drug-induced cell death, including gene mutations, changes in drug uptake, or activation of alternate signalling pathways. Even when initially responsive, breast cancer may return as drug-resistant metastatic disease, reducing the efficacy of subsequent treatments. This dynamic reflects an “arms race,” with clinicians constantly adjusting treatments to stay ahead of evolving cancer cells.

Drug resistance is not limited to breast cancer; it represents a critical challenge across many cancers, including lung cancer, where the problem is complex. Resistance can arise not only to initial therapies but also to drugs designed to overcome previous resistance, creating a vicious cycle that exemplifies the ongoing arms race with cancer. In advanced non-small-cell lung cancer (NSCLC), for example, tumours initially treated with the tyrosine kinase inhibitor (TKI) erlotinib often acquire the T790M mutation, rendering the drug ineffective. The next-generation TKI, osimertinib, is then deployed to target this mutation. However, resistance evolves again, with some tumours acquiring the C797S mutation, rendering osimertinib ineffective.

This pattern demonstrates the relentless nature of resistance evolution, as each treatment reshapes the tumour’s evolutionary landscape, selecting for new drug-resistant clones. Early studies using single-cell analysis have revealed that small populations of resistant cells often exist within tumours from the outset, even before treatment begins. These resistant subclones lie dormant and proliferate under selective pressure from therapies, ultimately driving relapse. As a result, each new generation of drugs provides only temporary benefits, leaving clinicians and researchers racing to develop new strategies before all treatment options are exhausted.

Combining treatments: The more, the merrier?

Using combination therapies at the start of treatment offers hope of overcoming drug resistance by attacking cancer through multiple pathways. For example, in breast cancer, combining targeted therapies such as trastuzumab—a drug that specifically targets the HER2 protein, which is overexpressed in some breast cancers—with chemotherapy has shown improved outcomes by curbing both tumour growth and metastasis simultaneously. By using drugs with different mechanisms, the chances of cancer cells developing resistance to several treatments at the same time can be reduced. However, research has found that outside of common growth pathways that cancer cells use, there are very few unique targets for treatment that can be combined effectively. This means that many treatment strategies end up overlapping, making them less effective. When different drugs target the same pathway, a mutation in that pathway can render all these drugs ineffective, as the cancer cells may adapt to resist multiple treatments at once.

Even when promising combinations are found, finding the right balance between effectiveness and safety is a significant challenge. For instance, combining the next-generation epidermal growth factor receptor (EGFR) inhibitor Osimertinib with chemotherapy can lead to better short-term results, but because chemotherapy has a narrow margin of safety range for clinical use, many patients who receive combinatorial therapy often experience significant side effects. Additionally, tumours with EGFR mutations usually produce fewer proteins that help the immune system recognise and attack cancer cells. This makes it more difficult to pair targeted therapies with immunotherapy. These challenges highlight how complicated it can be to find treatments that work well together while also being safe, but researchers continue to look for innovative ways to stay ahead of cancer’s ability to adapt.

Overcoming drug resistance: Thinking outside the box

While many new drugs are being developed to specifically target molecular mechanisms of drug resistance in cancer, researchers are also exploring creative strategies to tackle the problem of drug resistance. One innovative approach is adaptive therapy, pioneered by Professor Robert Gatenby and his team from Moffitt Cancer Centre in the US. This method acknowledges that cancer is constantly evolving, and instead of trying to eliminate every cancer cell right away, adaptive therapy aims to control the tumour by allowing some sensitive cancer cells to survive. The strategy avoids the risk of forcing cancer into a desperate state—akin to “a cornered rat fighting back”—where aggressive treatments push cells to mutate rapidly and evolve resistance, making them harder to overcome. By maintaining a balance between sensitive and resistant cells, adaptive therapy keeps the tumour in check over a longer period. It also minimises side effects through the use of lower doses and shorter treatment periods compared to conventional chemotherapy.

Another promising concept involves the use of selection gene drives, developed by researchers at Pennsylvania State University in the US. This approach employs the analogy of “suicide bombers” within the tumour. The engineered cancer cells are designed with two genetic switches. The first switch enables these cells to thrive and when chemotherapy is used, allowing them to become more prevalent in the tumour. As the chemotherapy continues, these cancer cells “evolve” to outnumber others. Once the first switch has ensured their dominance, the second switch is activated, prompting these cells to self-destruct. This not only eliminates the engineered cancer cells but also triggers the surrounding cancer cells to die as well, akin to collateral damage in an explosion. This method effectively introduces a “Trojan horse” subpopulation of engineered cells that prevents the expansion of incumbent resistant subpopulations by outcompeting them during treatment and killing them off subsequently.

Although adaptive therapy and selection gene drives are still being studied and tested, they represent significant innovations in cancer treatment strategies. These methods focus on outsmarting cancer’s ability to evolve and resist, potentially leading to better management of the disease. As research progresses, there is hope that these and other advancements will lead to more effective therapies free from resistance issues, offering new opportunities for patients fighting metastatic cancers, empowering them to face their futures with renewed hope rather than living in the persistent shadow of cancer relapse.

This article was first written in Mandarin and published in Lianhe Zaobao on 7 November 2024.