Five New Research Strategies Aim to Overcome Cancer Drug Resistance

Recent research has identified multiple new strategies to overcome cancer drug resistance, including a triple-drug combination that nearly eliminates resistant leukemia stem cells, a target for metastatic breast cancer, and an evolutionary approach to switching therapies.

In a study published in Science Advances, researchers at Thomas Jefferson University identified a three-drug combination that nearly eliminates cancer cells resistant to current treatments for acute myeloid leukemia (AML). The regimen pairs the investigational drug inobrodib with two FDA-approved drugs, venetoclax and gilteritnib. The three-drug combination produced more cancer cell death than any single drug or two-drug combination tested in mice, with roughly 10 times fewer leukemia stem cells remaining in bone marrow than with the next most effective therapy. The combination also triggered extensive cancer cell death in samples from AML patients. The team is working with clinicians, collaborators, and the drug manufacturer to explore a future clinical trial for patients with relapsed or treatment-resistant AML.

A Houston Methodist-led study published in Clinical Cancer Research analyzed 47 patients and 109 pretreatment metastatic lesions treated with trastuzumab deruxtecan (T-DXd) and identified S100–RAGE signaling as a key driver of early drug resistance in tumors. Blocking this signaling pathway made cancer cells sensitive to early-line treatment, and in metastatic lab models, the therapeutic combination significantly reduced metastatic lesion number, lesion size, and overall tumor burden. According to the Centers for Disease Control and Prevention, breast cancer is the second most common cancer among women in the United States and the second leading cause of cancer death among women, with metastatic breast cancer having the lowest survival rate.

Another study from researchers at City St George's, University of London suggests that doctors could improve cure rates by changing therapies before a tumor has a chance to recover, switching to another therapy while the tumor is still shrinking. This 'kick it while it's down' strategy is designed to address drug resistance, since waiting for a visible relapse gives surviving cancer cells more time to evolve. Mathematical models indicate that switching treatments before the tumor begins growing again could generally perform better than the standard of care, although a sequence of two treatments is likely to succeed only in relatively small tumors, while three or more treatments could eliminate larger tumors. The findings are based on mathematical modeling and require further testing, but three small clinical trials are already underway in soft-tissue cancer, prostate cancer, and breast cancer.

A study from the Hebrew University of Jerusalem, also published in Science Advances, found that cancer cells may damage their own DNA by forcing critical genes to operate at extreme levels. Powerful DNA control regions known as super-enhancers drive intense activity in growth-related genes, placing strain on the DNA and leading to double-strand breaks. The breaks clustered inside genes controlled by super-enhancers, and repeated cycles of breaking and repair can introduce errors, allowing mutations to accumulate. This self-inflicted damage may help tumors evolve, but it also creates a potential vulnerability: therapies might eventually be designed to disrupt the intense gene activity driven by super-enhancers or prevent tumor cells from repairing the resulting DNA damage.

Research published in the journal Cancer Research suggests that sildenafil, commonly known by its brand name Viagra, may help slow the spread of cancer by limiting the ability of cancer cells to use cholesterol—an essential component that helps them migrate and form new tumors. The drug's anti-metastatic effects could become even stronger when combined with statins, which reduce cholesterol production. Patients taking sildenafil showed improved survival rates, though scientists emphasize that more clinical studies are needed before Viagra can be recommended as a cancer treatment.